JP2015143265A - Process and intermediate for synthesis of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a process and intermediate for the synthesis of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds.SOLUTION: This invention discloses: a novel process to synthesize 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl (nnethyl)]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds, which may be used, for example, as NK-1 inhibitor compounds in pharmaceutical preparations; intermediates useful in the process; and processes for preparing the intermediates. Also disclosed is a process for removal of metals from N-heterocyclic carbene metal complexes. IM=102123.

Description

FIELD OF THE INVENTION This application relates to 8-[{1- (3,5-bis- (trifluoromethyl) phenyl) -ethoxy} -methyl] -8-phenyl-1,7-diaza-spiro [4.5]. It relates to processes useful in the preparation of decan-2-one compounds and intermediates useful in their synthesis, and the intermediate compounds prepared thereby.

BACKGROUND OF THE INVENTION The identification of any publication, patent or patent application in this section or any section of this application is not an admission that such publication is prior art to the present invention.

  Diazaspirodecan-2-one, such as 8-[{1- (3,5-bis- (trifluoromethyl) phenyl) -ethoxy} -methyl] -8-phenyl-1,7-diaza-spiro [ 4.5] decan-2-one, for example, (5S, 8S) -8-[{(1R) -1- (3,5-bis- (trifluoromethyl) phenyl) -ethoxy} -methyl] -8 -Preparation of phenyl-1,7-diazaspiro [4.5] decan-2-one (compound of formula I), the disclosure of which is incorporated herein by reference in its entirety, May 23, 2006 It is described in Patent Document 1 of the application.

特許文献１に記載されている該化合物は、タキキニン化合物として分類され、ニューロペプチドニューロキニン−１受容体の拮抗薬（本明細書では、「ＮＫ−１」受容体拮抗薬）である。その他のＮＫ_１受容体拮抗薬およびそれらの合成が記載されており、例えば、それぞれが参照により本明細書にそれら全体として組み込まれている、非特許文献１；非特許文献２；および非特許文献３ならびに特許文献２に記載されているものがある。式Ｉの化合物を調製するためのプロセスは、また、２００８年３月２０日出願の特許文献３にも開示されている。

The compound described in Patent Document 1 is classified as a tachykinin compound, and is an antagonist of the neuropeptide neurokinin-1 receptor (herein, “NK-1” receptor antagonist). Other NK ₁ receptor antagonists and their synthesis have been described, eg, Non-Patent Document 1; Non-Patent Document 2; and Non-Patent Documents, each of which is incorporated herein by reference in its entirety. 3 and Patent Document 2 are described. A process for preparing compounds of formula I is also disclosed in US Pat.

  “NK-1” receptor antagonists have been shown to be useful therapeutic agents for the treatment of, for example, pain, inflammation, migraine, vomiting and nociception. Among the many compounds disclosed in the aforementioned US Pat. No. 6,037,017 there are several novel diazaspirodecan-2-ones that are associated with any cause of vomiting and nausea such as anesthesia or chemotherapy Included are compounds of formula I that are useful in the treatment of vomiting (chemotherapy-induced nausea and vomiting, CINE herein) associated with recovery from treatment.

  The synthetic method for preparing the compound of formula I described in US Pat. No. 6,057,849 is 8-[{1- (3,5-bis- (trifluoromethyl) phenyl) -ethoxy} -methyl] -8-. Scheme A in the supply of phenyl-1,7-diaza-spiro [4.5] decan-2-one compounds is generally followed.

特許文献１に記載されている式Ｉの化合物を調製するためのプロセスは、市販の出発物質から１８の個別ステップにおいて行われ、特許文献１に記載されているそのプロセスの多くのステップにおいて、中間体化合物は、その後のステップで使用する前に、単離または単離して精製しなければならず、多くの場合その目的のためにはカラムクロマトグラフィーを利用する。一般に、特許文献１に記載されている合成スキームは、不要な異性体の生成で、望まれるより大きい割合の出発化合物および中間体化合物を消費する。

The process for preparing the compound of formula I described in US Pat. No. 6,057,038 is performed in 18 individual steps from commercially available starting materials, and in many steps of the process described in US Pat. The body compound must be isolated or isolated and purified before use in subsequent steps, often utilizing column chromatography for that purpose. In general, the synthetic scheme described in US Pat. No. 6,057,831 consumes a greater proportion of the starting and intermediate compounds desired with the formation of unwanted isomers.

  The process for preparing compounds of formula I described in US Pat.

スキームＢに記載されているプロセスは、スキームＡと比較して含まれているステップの数が約２分の１であり、スキームＡより大きい収率で該化合物を生成するが、両方のスキームとも、ジアステレオ選択性が不十分であることが欠点である。

The process described in Scheme B includes approximately one-half the number of steps involved compared to Scheme A, and produces the compound in a greater yield than Scheme A, but both schemes The disadvantage is that the diastereoselectivity is insufficient.

  Therefore, what is needed is a more convergent and efficient process with improved diastereoselectivity.

US Pat. No. 7,049,320 International Publication No. 05/130038 US Patent Application Publication No. 2008/003640

Wu et al., Tetrahedron (2000) 56, 3043-3051. Rombouts et al., Tetrahedron Letters (2001) 42, 7397-7399. Rogiers et al., Tetrahedron (2001) 57, 8971-8981.

  What is needed is a 8-[{1 which provides a reaction scheme with a reduced number of steps, increased diastereoselectivity, and allows practical scale-up to batch sizes suitable for industrial scale preparation. Synthesis for preparing-(3,5-bis- (trifluoromethyl) phenyl) -ethoxy} -methyl] -8-phenyl-1,7-diaza-spiro [4.5] decan-2-one compounds It is a scheme.

  These and other objects are advantageously provided by the present invention, which in one aspect, as illustrated in Scheme I, (5S, 8S) -8-[{1- (R)-(3 , 5-Bis- (trifluoromethyl) phenyl) -ethoxy} -methyl] -8-phenyl-1,7-diaza-spiro [4.5] decan-2-one hydrochloride monohydrate, ie Formula VIII This is a process for producing the compound.

ここで、該プロセスは、
ａ）式ＶＩａの塩化合物、［５（Ｒ）−［［［１（Ｓ）−［［１（Ｒ）−［３，５−ビス（トリフルオロメチル）−フェニル］エトキシ］−メチル］−１−フェニル−２−プロペニル］アミノ］メチル］−５−エテニル−２−ピロリジノン］［塩２］（ただし、「塩２」は、式ＶＩａの化合物中の塩基性官能基、例えば、窒素の電子対に結合し、それ故アンモニウムカチオンを形成し、そこで配位しているアニオン部分、例えば、酸の共役塩基と会合し、閉環メタセシス触媒を用いて式ＶＩａのジエン−アミン塩化合物を環化している少なくとも１つのプロトンを表している）を提供するステップ、
ｂ）ステップ（ａ）からの環化生成物を塩に変換して式ＶＩＩの化合物、［（５Ｒ，８Ｓ）−８−［１−（Ｒ）−（３，５−ビス−トリフルオロメチル−フェニル）−エトキシメチル］−８−フェニル−１，７−ジアザスピロ［４．５］デカ−９−エン−２−オン］塩３（ただし、「塩３」は、式ＶＩＩの化合物中の塩基性官能基に結合し、そこで配位しているアニオン部分と会合している少なくとも１つのプロトンを表している）を得るステップ、
ｃ）ステップ（ｂ）で提供された式ＶＩＩの塩化合物を、例えば、式Ｍ−ＯＨであって「Ｍ」がアルカリ金属またはアルカリ土類金属である水酸化物塩基により処理して式ＶＩＩｂの対応する遊離塩基化合物を提供し、この式ＶＩＩｂの遊離塩基化合物を還元し、その還元生成物をＨＣｌにより処理して、式ＶＩＩＩの１，７−ジアザスピロ［４．５］デカ−２−オン塩酸塩水和物を得るステップ、および
ｄ）場合によって式ＶＩＩＩのＨＣｌ塩を再結晶させ、それによって式Ｉａの化合物を得るステップ
を含む。

Here, the process is
a) a salt compound of formula VIa, [5 (R)-[[[1 (S)-[[1 (R)-[3,5-bis (trifluoromethyl) -phenyl] ethoxy] -methyl] -1 -Phenyl-2-propenyl] amino] methyl] -5-ethenyl-2-pyrrolidinone] [salt 2] (wherein "salt 2" is a basic functional group in the compound of formula VIa, for example, an electron pair of nitrogen , Thus forming an ammonium cation, which associates with the anion moiety coordinated there, eg, the conjugate base of the acid, and cyclizes the diene-amine salt compound of formula VIa using a ring-closing metathesis catalyst. Providing at least one proton),
b) The cyclized product from step (a) is converted to a salt to give a compound of formula VII, [(5R, 8S) -8- [1- (R)-(3,5-bis-trifluoromethyl- Phenyl) -ethoxymethyl] -8-phenyl-1,7-diazaspiro [4.5] dec-9-en-2-one] salt 3 (wherein “salt 3” is the basic in the compound of formula VII Obtaining at least one proton bound to a functional group and associated with an anionic moiety coordinated therewith,
c) Treating the salt compound of formula VII provided in step (b) with a hydroxide base of formula M-OH, where “M” is an alkali metal or alkaline earth metal, for example of formula VIIb The corresponding free base compound is provided, the free base compound of formula VIIb is reduced and the reduction product is treated with HCl to give 1,7-diazaspiro [4.5] dec-2-one hydrochloride of formula VIII Obtaining a salt hydrate, and d) optionally recrystallizing the HCl salt of formula VIII, thereby obtaining a compound of formula Ia.

  In some embodiments of Scheme I, preferably the reduction in step “c” for the salt compound of formula VII is carried out without liberating the free base form from the reduced form produced thereby. The salt product is recovered without precipitating the salt of the free base reduction product.

  In some embodiments of the present invention, preferably step (a) of Scheme I is carried out in the presence of a sufficient amount of added acid to reduce the amount of ring-closing metathesis catalyst employed (the amount of catalyst present). To do. In some embodiments of Scheme I using an added acid in step (a), preferably an acid having a pKa that is approximately equal to or less than that of the diene compound of formula VI that is cyclized in the reaction, eg, 6. An acid having a pKa of 5 or less is used. In some embodiments of Scheme I using added acid in step (a), the acid includes (i) a mineral acid, such as HCl, HBr, or sulfuric acid, (ii) an organic monobasic acid or dibasic acid For example, acetic acid, propaneic acid, maleic acid, fumaric acid, trifluoroacetic acid, or tartaric acid, or (iii) sulfonic acids such as alkyl sulfonic acids or substituted alkyl sulfonic acids such as methane Preferably, it is a sulfonic acid, 4-methylbenzenesulfonic acid monohydrate, or trifluoromethanesulfonic acid, or an aromatic arylsulfonic acid, such as p-toluenesulfonic acid or substituted arylsulfonic acid. In some embodiments utilizing an excess of step 2 acid, the acid is preferably an aryl sulfonic acid, more preferably p-tolyl sulfonic acid. In some embodiments utilizing an excess of acid from Step 2, an amount of acid from about 0.1 to about 2.0 equivalents relative to the amount of substrate initially present in the reaction mixture may be added. preferable.

  In some embodiments of Scheme I, the cyclization reaction in step (a) is preferably performed by the process illustrated in Scheme Ia.

式中、
構造ＸＸの化合物の点線は、任意の二重結合を表し、「塩２」は、上で定義したものと同じであり、
Ａｒは、アリール部分、例えば、フェニルまたはメシチル（２，４，６−トリメチルフェニル）であり、
Ｌは、Ｐ（Ｒ^２ａ）_３（ただし、Ｒ^２ａは、独立して選択され、フェニル、アリール、アルコキシルフェニルまたはアルキルである）であり、
Ｍは、ルテニウム、パラジウム、またはイリジウムである金属であり、
Ｘは、ハロゲンであり、
Ｒは、Ｈ、アリール、またはヘテロアリールであり、
ＨＸは、好ましくは、「Ｘ」が、ハロゲン、例えば、クロリド、ブロミド、またはヨウダイド；サルフェート；サルファイト；またはスルホネート部分、例えば、メシレート、トリフルオロメチルスルホネート、またはアリールスルホネート、例えば、トシレート、である酸種であり、
該プロセスは、
（ｉ）式ＶＩの第二級アミン塩を式ＨＸの酸と接触させるステップ、
（ｉｉ）ステップ（ｉ）からの混合物に閉環メタセシス触媒を、好ましくは、使用される式ＶＩの化合物の量に対して準化学量論的である量で加えるステップ、および
（ｉｉｉ）その混合物を加熱して式ＶＩの化合物を環化させるステップ
を含む。

Where
The dotted line of the compound of structure XX represents any double bond, “Salt 2” is the same as defined above,
Ar is an aryl moiety, such as phenyl or mesityl (2,4,6-trimethylphenyl);
L is P (R ^2a ) ₃ where R ^2a is independently selected and is phenyl, aryl, alkoxylphenyl or alkyl;
M is a metal that is ruthenium, palladium, or iridium;
X is a halogen,
R is H, aryl, or heteroaryl;
HX is preferably “X” is a halogen, such as chloride, bromide, or iodide; sulfate; sulfite; or a sulfonate moiety, such as mesylate, trifluoromethyl sulfonate, or aryl sulfonate, such as tosylate. Acid species,
The process
(I) contacting a secondary amine salt of formula VI with an acid of formula HX;
(Ii) adding a ring-closing metathesis catalyst to the mixture from step (i), preferably in an amount that is substoichiometric to the amount of compound of formula VI used; and (iii) adding the mixture Heating to cyclize the compound of formula VI.

  In some embodiments of Scheme Ia, the ring-closing metathesis catalyst used in the reaction is of the formula XXa, XXb, or XXd:

の化合物から選択され、式中、金属（Ｍ）は、好ましくは、８個の「ｄ」軌道電子を提供しているホルマール酸化状態の遷移金属（８族遷移金属、例えば、ルテニウム、パラジウムまたはイリジウム、あるいは６族遷移金属、例えば、モリブデン）であり、「Ｌ^１」は、かなりのπ逆供与能を有するσ結合した炭素配位子、例えば、式ＸＸａおよびＸＸｄの化合物中に示されているイミダゾール配位子であり、Ｌ^２は、単座配位子、例えば、ホスフィン配位子、例えば（Ｃｙ_３Ｐ）であるか、または図のように、Ｌ^２は、場合によって、カルベン配位子（ｌｌｉｇａｎｄ）のＲ^３置換基に結合しており、場合によってＲ^３を介してカルベン配位子に結合しているときは、Ｌ^２とＲ^３との間の半円の点線によって示されているように、Ｌ^２は、二座配位子を形成し、Ｌ^２は、キレート化部分、例えば、酸素部分、亜リン酸部分（ｐｈｏｓｐｈｏｒｏｕｓ ｍｏｉｅｔｙ）、または窒素部分、例えば、式ＸＸｄの触媒中に示されているアルコキシベンジリデン二座配位子、例えばイソプロポキシ（ｉｓｏｐｒｏｘｙ）−ベンジリデン配位子中の酸素部分であり、Ｒ^１は、アリール、ヘテロアリール、アルキル、または水素から独立して選択され、Ｒ^３は、アルキルへテロアリールまたはアリール、例えば、フェニル部分であり、またはＲ^３が、Ｌ^２に結合していないときは、Ｒ^３は、水素であり得、（Ｘ）は、強酸の共役塩基であり、好ましくは、Ｘは、スルホネート部分、例えば、トシレートであるか、またはハロゲン部分、例えば、クロリドである。

Wherein the metal (M) is preferably a transition metal in a formal oxidation state (e.g., a group 8 transition metal such as ruthenium, palladium or iridium) providing eight “d” orbital electrons. Or a Group 6 transition metal, eg, molybdenum), where “L ¹ ” is shown in a σ-bonded carbon ligand, eg, compounds of formula XXa and XXd, that have significant π reverse donating ability An imidazole ligand and L ² is a monodentate ligand, eg, a phosphine ligand, eg (Cy ₃ P), or, as shown, L ² is optionally a carbene ligand It is bound to ^{R 3} substituent (lligand), when the case is bonded to the carbene ligand via the ^{R 3} by, indicated by the dotted semicircle between ^{L 2} and ^{R 3} as are, L Forms a bidentate ligand, ^{L 2} is a chelating moiety, for example, oxygen partial phosphite moiety (phosphorous moiety), or nitrogen moiety, for example, alkoxy, shown in the catalyst of formula XXd A benzylidene bidentate ligand, such as an oxygen moiety in an isopropoxy-benzylidene ligand, R ¹ is independently selected from aryl, heteroaryl, alkyl, or hydrogen, and R ³ is alkyl When heteroaryl or aryl, eg, a phenyl moiety, or R ³ is not attached to L ² , R ³ can be hydrogen and (X) is a strong acid conjugate base, preferably , X is a sulfonate moiety, such as tosylate, or a halogen moiety, such as chloride.

  Of course, in Scheme I shown above, the compound of formula Ia is the (S, S, R) enantiomer, but using the process of the present invention, the starting material of the appropriate stereoisomeric structure Is used as an isomer of a compound of formula I, i.e.

の全てを調製することができる。

All of these can be prepared.

  In some embodiments of the invention, the compound of formula VIa used in Scheme I is preferably provided by the process of Scheme Iaa.

ここで、該プロセスは、
ａ）式ＩＩＩのピラゾロ−５−オンを提供するステップ、
ｂ）式ＩＶの遊離塩基化合物、［（１Ｓ）−１−（｛（１Ｒ）−１−［３，５−ビス（トリフルオロメチル）フェニル］エトキシ｝メチル）−１−フェニルプロプ−２−エニル）アミンを提供し、それをステップ（ａ）で提供した式ＩＩＩの化合物と反応させて、式Ｖのジエン−イミン、［（（５Ｒ）−５−（（Ｚ）−｛［（１Ｓ）−１−（｛（１Ｒ）−１−［３，５ビス（トリフルオロメチル）−フェニル］−エトキシ｝メチル）−１−フェニルプロプ−２−エン−１イル］イミノ｝メチル）−５−ビニルピロリジン−２−オン）］を生じさせるステップ、
ｃ）ステップ（ｂ）で調製した式Ｖのジエン−イミン化合物を還元して、対応するジエン−アミン化合物を得、それを対応する式ＶＩの塩化合物、［５（Ｒ）−［［［１（Ｓ）−［［１（Ｒ）−［３，５−ビス（トリフルオロメチル）−フェニル］エトキシ］−メチル］−１−フェニル−２−プロペニル］アミノ］メチル］−５−エテニル−２−ピロリジノン］［塩２］（ただし、「塩２」は、式ＶＩの化合物中の塩基性官能基、例えば、該化合物における窒素原子中の電子対に結合し、そこで配位しているアニオン部分と会合している少なくとも１つのプロトンを表す）に変換するステップ
を含む。

Here, the process is
a) providing a pyrazolo-5-one of formula III;
b) Free base compound of formula IV, [(1S) -1-({(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} methyl) -1-phenylprop-2-enyl ) An amine, which is reacted with the compound of formula III provided in step (a) to give the diene-imine of formula V, [((5R) -5-((Z)-{[(1S)- 1-({(1R) -1- [3,5bis (trifluoromethyl) -phenyl] -ethoxy} methyl) -1-phenylprop-2-en-1yl] imino} methyl) -5-vinylpyrrolidine 2-on))],
c) Reduction of the diene-imine compound of formula V prepared in step (b) to give the corresponding diene-amine compound, which is converted to the corresponding salt compound of formula VI, [5 (R)-[[[1 (S)-[[1 (R)-[3,5-Bis (trifluoromethyl) -phenyl] ethoxy] -methyl] -1-phenyl-2-propenyl] amino] methyl] -5-ethenyl-2- [Pyrrolidinone] [Salt 2] (wherein "Salt 2" is a basic functional group in the compound of formula VI, for example, an anion moiety that binds to and coordinates with an electron pair in the nitrogen atom of the compound) Representing at least one proton associated).

  In some embodiments of the invention, in step (a) of Scheme Iaa, a pyrazolo-5-one compound of formula III is converted to a compound of formula II: (3R)-(1,1-dimethylethyl) -7aR— It is preferred to provide ethenyltetrahydro-1 (R / S) -hydroxy-3H, 5H-pyrrolo [1,2-c] oxazol-5-one by treatment with a suitable base such as triethylamine. In some embodiments of the invention, in step (b) of Scheme Iaa, the free base compound of formula IV is converted to formula IVa

（式中、塩１は、塩基性官能基、例えば、式ＩＶａの化合物中のアミン置換基に結合し、そこで配位しているアニオン部分と会合している少なくとも１つのプロトンを表す）
の対応する塩化合物を、水溶性塩基、例えば、水酸化ナトリウムで処理することによって提供するのが好ましい。式ＩＶａの塩化合物を調製するための適当な酸は、例えば、有機酸、例えば、マレイン酸、コハク酸、またはリンゴ酸、および無機酸、例えば、ＨＣｌ、ＨＢｒ、およびＨＩである。

Wherein salt 1 represents at least one proton associated with a basic functional group, eg, an amine substituent in a compound of formula IVa, and associated with the anionic moiety coordinated there.
Is preferably provided by treatment with a water-soluble base such as sodium hydroxide. Suitable acids for preparing the salt compounds of formula IVa are, for example, organic acids such as maleic acid, succinic acid or malic acid, and inorganic acids such as HCl, HBr and HI.

  In some embodiments of the present invention, preferably the ring-closing metathesis catalyst in step 2 is a ring-closing metathesis catalyst of formula XX as described in Scheme 4 (below).

  In some embodiments of the present invention, preferably the intermediate of formula IV is prepared using steps 2-3 of Scheme 2 and other processes. In some embodiments, preferably an intermediate of structure X for use in preparing a compound of formula IV is provided as shown in steps 2-1 and 2-2 of Scheme II. To do.

ここで、該プロセスは、
ステップ２−１：
ＰｈＣＨ（ＯＣＨ_３）_２で示される２−フェニルグリシン誘導体を環化して式ＩＸのオキサゾリジノンを得るステップ（ただし、Ｃｂｚは、カルボキシベンジル−アミン保護基である）、
ステップ２−２：
式ＩＸの該化合物を［３，５−ビス（トリフルオロメチル）フェニル］−エトキシ−ブロモメチルエーテルと組み合わせて式Ｘのラクトンを得るステップ、
ステップ２−３：
式Ｘの該ラクトンを還元して式ＸＩのラクトールにするステップ、
ステップ２−４：
式ＸＩの該ラクトールの環を開いて式ＸＩＩのアルデヒドを得るステップ、
ステップ２−５：
式ＸＩＩの該アルデヒドを式ＸＩＩＩのアルケニルアミンに変換するステップ、および
ステップ２−６：
式ＸＩＩＩの該アルケニルアミンを脱保護し、それによって得られた対応する遊離塩基を式ＩＶの塩に変換するステップ
を含む。

Here, the process is
Step 2-1
Cyclizing a 2-phenylglycine derivative represented by PhCH (OCH ₃ ) ₂ to give an oxazolidinone of formula IX (where Cbz is a carboxybenzyl-amine protecting group);
Step 2-2:
Combining the compound of formula IX with [3,5-bis (trifluoromethyl) phenyl] -ethoxy-bromomethyl ether to give a lactone of formula X;
Step 2-3:
Reducing the lactone of formula X to lactol of formula XI;
Step 2-4:
Opening the lactol ring of formula XI to obtain an aldehyde of formula XII;
Step 2-5:
Converting the aldehyde of formula XII to an alkenylamine of formula XIII, and steps 2-6:
Deprotecting the alkenylamine of formula XIII and converting the corresponding free base obtained thereby to a salt of formula IV.

  In some embodiments of the process of the present invention, preferably the intermediate of formula II is prepared according to the process shown in Scheme 3.

ここで、該プロセスは、
ステップ３−１：
ピログルタミン酸を、トリメチルアセトアルデヒドおよびメタンスルホン（ｍｅｔｈａｎｅｓｕｌｆｉｏｎｉｃ）酸により処理して式ＸＩＶの（３Ｒ，６Ｓ）−３−ｔｅｒｔ−ブチルジヒドロ−１Ｈ−ピロロ［１，２−ｃ］［１，３］オキサゾール−１，５（６Ｈ）−ジオンを得るステップ、
ステップ３−２：
式ＸＩＶの該ピロロ［１，２−ｃ］［１，３］オキサゾール−１，５（６Ｈ）−ジオンをギ酸メチルと反応させて式ＸＶのピロロ［１，２−ｃ］オキサゾール−７ａ−カルバルデヒドを得るステップ、
ステップ３−３：
式ＸＶの該カルバルデヒドを、式ＸＶＩの７ａ−ビニル−ジヒドロ−ピロロ［１，２−ｃ］［１，３］オキサゾール−１，５−ジオンに変換するステップ、および
ステップ３−４：
式ＸＶＩの該ジオンを還元して式ＩＩの（３Ｒ）−１，１−ジメチル−７ａ（Ｒ）−エテニル−テトラヒドロ−１（Ｒ／Ｓ）−ヒドロキシ−３Ｈ，５Ｈ＝ピロロ［１，２−ｃ］オキサゾール−５−オンを得るステップ
を含む。

Here, the process is
Step 3-1
Pyroglutamic acid is treated with trimethylacetaldehyde and methanesulfonic acid to give (3R, 6S) -3-tert-butyldihydro-1H-pyrrolo [1,2-c] [1,3] oxazole- of formula XIV Obtaining 1,5 (6H) -dione;
Step 3-2:
The pyrrolo [1,2-c] [1,3] oxazole-1,5 (6H) -dione of formula XIV is reacted with methyl formate to form pyrrolo [1,2-c] oxazole-7a-carba of formula XV. The steps to get rudehide,
Step 3-3:
Converting the carbaldehyde of Formula XV to 7a-vinyl-dihydro-pyrrolo [1,2-c] [1,3] oxazole-1,5-dione of Formula XVI, and Step 3-4:
Reduction of the dione of formula XVI to (3R) -1,1-dimethyl-7a (R) -ethenyl-tetrahydro-1 (R / S) -hydroxy-3H, 5H = pyrrolo [1,2- c] obtaining oxazol-5-one.

  Another aspect of the invention relates to the following novel intermediates used or prepared in the processes represented in Schemes 1-3.

スキーム４は、閉環が完了した後で反応混合物からメタセシス触媒を除去するための化学プロセスを図示している。本発明のいくつかの実施形態において、好ましくは、環化反応で使用したメタセシス触媒と会合している金属の除去に対しては、スキーム１に示されている反応ステップ２の終わりにスキーム４に図示されている化学プロセスを採用する。それ故、スキーム４は、式ＸＸａ’のメタセシス触媒の除去を図示しており、好ましくは式ＸＸａ’の錯体は、Ｎ−複素環カルベン（ｃａｒｂｉｎｅ）金属錯体であるが、当然のことながら、該プロセスは、任意の金属メタセシス触媒を反応混合物から化学的に除去するために採用することができる。

Scheme 4 illustrates a chemical process for removing the metathesis catalyst from the reaction mixture after ring closure is complete. In some embodiments of the present invention, preferably for the removal of the metal associated with the metathesis catalyst used in the cyclization reaction, at the end of reaction step 2 shown in Scheme 1, scheme 4 The chemical process shown is employed. Therefore, Scheme 4 illustrates the removal of the metathesis catalyst of formula XXa ′, preferably the complex of formula XXa ′ is an N-heterocyclic carbene metal complex, although it is understood that The process can be employed to chemically remove any metal metathesis catalyst from the reaction mixture.

式中、
点線は、任意の結合を表し、
Ａｒは、フェニル、２，４，６−トリメチルフェニル、または２，６−ジメチルフェニルであり、
Ｍは、好ましくは、８個の「ｄ」軌道電子を提供しているホルマール酸化状態の遷移金属（８族遷移金属、例えば、ルテニウム、パラジウムまたはイリジウム）または６族遷移金属、例えば、モリブデン（ｍｏｌｙｂｅｄｉｎｕｍ）であり、
Ｌ^２は、ホスフィン配位子、例えば、「Ｒ」がフェニルアリール、またはアルキルであるＰ（Ｒ）_３、例えば、（Ｃｙ）_３Ｐであり、あるいは場合によって、Ｌ^２は、Ｌ^２とＲ^３との間の半円の点線によって示されているように、Ｒ^３を介してカルベン置換基に結合して二座配位子を形成しており、その場合、Ｌ^２は、キレート化部分、例えば、酸素部分、亜リン酸部分、または窒素部分、例えば、式ＸＸｄ（本明細書中）の触媒中に示されているイソプロポキシ−ベンジリデン二座配位子中の酸素部分であり、
Ｒ^１は、アリール、アルキル、または水素から独立して選択され、
Ｒ^２は、Ｈ、ＯＨ、または＝Ｏであり、
Ｒ^３は、アリール、アルキルまたはフェニル部分であり、またはＬ^２が、Ｒ^３に結合していない場合は、Ｈであり、
（Ｘ）は、強酸の共役塩基、例えば、ハロゲン、サルフェート、サルファイトまたはスルホネートアニオンであり、好ましくは、「Ｘ」は、スルホネートアニオン、例えば、トシレートであるか、またはハロゲン部分、例えば、クロリドまたはブロミドであり、
該プロセスは、
（ｉ）還元試薬、好ましくは、メタ重亜硫酸ナトリウム（Ｎａ_２Ｓ_２Ｏ_５）、亜硫酸ナトリウム（Ｎａ_２ＳＯ_３）、亜硫酸水素ナトリウム（ＮａＳＯ_３Ｈ）、次亜リン酸（ホスフィン酸、Ｈ_３ＰＯ_２）、ギ酸ナトリウム（ＮａＯＣＨＯ）または亜リン酸ナトリウム塩（ＮａＨ_２ＰＯ_３）、または２つ以上の混合物である還元試薬の水溶液の混合物を、水非混和性の有機溶媒と式［ＸＸ］、［ＸＸａ］、［ＸＸｂ］または［ＸＸｄ］の少なくとも１つのＮ−複素環カルベン金属錯体とを含む溶液の存在下で加熱するステップ、および
（ｉｉ）加熱ステップ（ｉ）の後で、（ａ）該金属錯体が不溶性の場合は濾過により、または（ｂ）該金属錯体が溶解性の場合は該金属錯体を水層中に吸収させ、有機層と水層とを分離することによって、有機層から式ＭＬ_２の金属錯体を分離するステップ
を含む。

Where
The dotted line represents any bond,
Ar is phenyl, 2,4,6-trimethylphenyl, or 2,6-dimethylphenyl;
M is preferably a transition metal in a formal oxidation state (group 8 transition metal, such as ruthenium, palladium or iridium) or group 6 transition metal, such as molybdenum, providing eight “d” orbital electrons. ) And
L ² is a phosphine ligand, eg, P (R) ₃ , eg, (Cy) ₃ P, where “R” is phenylaryl, or alkyl, or optionally L ² is L ² and R Is bound to the carbene substituent via R ³ to form a bidentate ligand, as indicated by the semicircle dotted line between ³ and ³ , in which case L ² is a chelating moiety For example, an oxygen moiety, a phosphite moiety, or a nitrogen moiety, such as an oxygen moiety in an isopropoxy-benzylidene bidentate ligand shown in a catalyst of formula XXd (herein),
R ¹ is independently selected from aryl, alkyl, or hydrogen;
R ² is H, OH, or ═O,
R ³ is an aryl, alkyl or phenyl moiety, or H when L ² is not bound to R ³ ;
(X) is a conjugate base of a strong acid, such as a halogen, sulfate, sulfite or sulfonate anion, preferably “X” is a sulfonate anion, such as tosylate, or a halogen moiety, such as chloride or Bromide,
The process
(I) A reducing reagent, preferably sodium metabisulfite (Na ₂ S ₂ O ₅ ), sodium sulfite (Na ₂ SO ₃ ), sodium bisulfite (NaSO ₃ H), hypophosphorous acid (phosphinic acid, H ₃ PO ₂ ), sodium formate (NaOCHO) or sodium phosphite salt (NaH ₂ PO ₃ ), or a mixture of two or more aqueous solutions of reducing reagents is mixed with a water-immiscible organic solvent and the formula [XX] Heating in the presence of a solution comprising at least one N-heterocyclic carbene metal complex of [XXa], [XXb] or [XXd], and (ii) after the heating step (i), (a When the metal complex is insoluble, it is filtered, or (b) when the metal complex is soluble, the metal complex is absorbed in the water layer, and the organic layer and the water layer are separated. I, comprising the step of separating the metal complexes of formula ML ₂ from the organic layer.

In some embodiments, preferably the process of Scheme 4 comprises a phase transfer catalyst, such as a quaternary ammonium salt, such as the formula [(R ^a3 ) ₄ N] ⁺ X ⁻ , where R ^a3 is In the presence of a quaternary ammonium salt of alkyl, such as n-butyl-, where X is a halide, sulfonate, or nitrate.

の化合物を製造するためのプロセスであって、
前記プロセスが、
（ａ）式ＶＩａ：

の塩化合物を、閉環メタセシス触媒の存在下および場合によって追加の酸の存在下で環化し、それによって、式ＶＩＩｂ、

の対応するジアザスピロデセン−オン（ｄｉａｚａｓｐｉｒｏｄｅｃｅｎｅ−ｏｎｅ）化合物を形成するステップと、
（ｂ）ステップ「ａ」からの式ＶＩＩｂの化合物を式ＶＩＩ、

の塩化合物に変換し、式ＶＩＩの前記塩化合物をステップ（ｃ）に提供するステップであって、ここで、前記式の「塩３」は、式ＶＩＩの前記化合物中の塩基性官能基に結合し、そこで配位しているアニオン部分と会合している少なくとも１つのプロトンを表す、ステップと、
（ｃ）ステップ（ｂ）からの式ＶＩＩの前記化合物を還元して式ＶＩＩＩ、

の化合物を得るステップと、
（ｄ）場合によって式ＶＩＩＩａの化合物のＨＣｌ塩を沈殿させて式ＶＩＩＩ、

の塩化合物を得、場合によって前記沈殿させた塩形態を再結晶させて式Ｉａ、

の化合物を得るステップと
を含む、プロセス。
（項目２）
ステップ（ａ）が、最大２当量までの追加の４−メチルベンゼンスルホン酸一水和物の存在下で行われる、項目１に記載のプロセス。
（項目３）
ステップ（ａ）の後でありかつステップ（ｂ）の前に、（ｉ）反応混合物を、還元試薬を含む水相と前記メタセシス触媒を還元するのに適切な条件下で接触させるステップと、（ｉｉ）前記反応混合物を、前記水相および還元ステップ（ｉ）の間に形成されたあらゆる沈殿物から分離するステップとを含む還元ステップをさらに含む、項目１または２のいずれかに記載のプロセス。
（項目４）
前記還元ステップのパート（ｉ）の前記水相が、相間移動触媒をさらに含む、項目３に記載のプロセス。
（項目５）
前記相間移動触媒が、第四級アンモニウム塩である、項目４に記載のプロセス。
（項目６）
前記閉環メタセシス触媒が、８族遷移金属または６族遷移金属およびカルベン配位子を含む、項目１から５のいずれかに記載のプロセス。
（項目７）
前記メタセシス触媒が、
（ｉ）式ＸＸａ、

の触媒であって、式中、
点線は、任意の結合を表し、
Ａｒは、フェニル、２，４，６−トリメチルフェニル、または２，６−ジメチルフェニルであり、
Ｌ^２は、Ｒ^３に結合していないときは（Ｌ^２とＲ^３の間の半円の点線は任意の結合を示している）、ホスフィン配位子であり、Ｌ^２とＲ^３の間で半円の任意の結合の点線により示されているようにＲ^３に結合しているときは、Ｌ^２はＲ^３と二座配位子を形成しており、Ｌ^２は、さらなる置換基を有するかもしくは有さない酸素部分、亜リン酸部分（ｐｈｏｓｐｈｏｒｏｕｓ ｍｏｉｅｔｙ）、または窒素部分であり、
Ｒ^１は、アリール、アルキル、または水素から独立して選択され、
Ｒ^３は、アルキル部分またはアリール部分であり、または、Ｒ^３がＬ^２に結合していないとき、Ｒ^３は、アルキル部分、アリール部分、または水素原子であり、
（Ｘ）は、強酸の共役塩基であり、
Ｍは、ルテニウム、パラジウム、またはイリジウムである、
触媒、
（ｉｉ）式ＸＸ、

の触媒であって、式中、
金属（Ｍ）は、ルテニウム、パラジウム、イリジウム、またはモリブデンであり、
（Ｌ）は、（ｉ）ホスフィン配位子、または（ｉｉ）キレート化配位子であり、
Ｘは、強酸の共役塩基であり、
Ｒ^１およびＲ^２は、それぞれ独立して、Ｈ、フェニル、ハロゲンまたはアルキルである、
触媒、あるいは
（ｉｉｉ）式ＸＸｄ、

の触媒であって、式中、
点線は、任意の二重結合を表しており、
（Ｍ）は、モリブデン、ルテニウム、パラジウムまたはイリジウムであり、
Ｒ^１は、独立して、アリール、アルキル、または水素であり、
Ａｒは、アリールまたはベンジルであり、
Ｘは、ハロゲン部分またはスルホネート部分である、
触媒
である、項目６に記載のプロセス。
（項目８）
前記メタセシス触媒が、式ＸＸｄ１：

の化合物であり、式中、「Ｍｅｓ」は、２，４，６−トリメチルフェニル部分である、項目７に記載のプロセス。
（項目９）
前記メタセシス触媒が、式ＸＸｄ２：

の触媒であり、式中、「Ｍｅｓ」は、２，４，６−トリメチルフェニル部分である、項目６に記載のプロセス。
（項目１０）
前記メタセシス触媒が、式ＸＸｄ３：

の化合物であり、式中、「Ｍｅｓ」は、２，４，６−トリメチルフェニル部分である、項目９に記載のプロセス。
（項目１１）
前記メタセシス触媒が、式ＸＸｄ４：

の化合物である、項目９に記載のプロセス。
（項目１２）
ステップ（ａ）の後で使用される前記還元試薬が、（ｉ）Ｎａ_２Ｓ_２Ｏ_５、Ｎａ_２ＳＯ_３、ＮａＳＯ_３Ｈ、ＮａＯＣ（Ｏ）Ｈ、またはＮａＨ_２ＰＯ_３のうちの１つまたは複数、（ｉｉ）亜リン酸、（ｉｉｉ）水素化ナトリウム、水素化ホウ素ナトリウム、または水素化アルミニウムリチウムのうちの１つまたは複数、（ｉｖ）水素と金属水素化触媒とで行われる還元、（ｖ）アスコルビン酸またはシュウ酸、（ｖｉ）過酸化水素、あるいは（ｖｉｉ）銅、亜鉛、鉄またはマグネシウム金属のうちの１つまたは複数、である、項目２から１１のいずれかに記載のプロセス。
（項目１３）
前記還元試薬が、メタ重亜硫酸ナトリウム（Ｎａ_２Ｓ_２Ｏ_５）、亜硫酸ナトリウム（Ｎａ_２ＳＯ_３）、亜硫酸水素ナトリウム（ＮａＨＳＯ_３）、ギ酸ナトリウム（ＮａＯＣ（Ｏ）Ｈ）、次亜リン酸（ホスフィン酸、Ｈ_３ＰＯ_２）、または亜リン酸ナトリウム塩（ＮａＨ_２ＰＯ_３）、あるいはそれらの２つ以上の混合物である、項目１２に記載のプロセス。
（項目１４）
相間移動触媒が、前記メタセシス還元ステップ中に含められ、前記相間移動触媒が、式（ＣＨ_３（ＣＨ_２）_３）_４Ｎ^＋Ｘ⁻を有し、式中、「Ｘ⁻」は、Ｃｌ⁻、Ｂｒ⁻、Ｆ⁻、Ｉ⁻ＨＳＯ_４ ⁻、または２分の１当量の（ＳＯ_４ ^−２）である、項目４から１１のいずれかに記載のプロセス。
（項目１５）
前記式ＶＩの化合物が、スキームＡａ：

の中に図示されているプロセスによって提供され、
ここで、前記プロセスが、
（ｉ）第三級アミンの存在下で水混和性の溶媒中に式ＩＩＩの遊離塩基化合物を提供するステップと、
（ｉｉ）ステップ（ｉ）からの溶液を式ＩＶの遊離塩基化合物と混合し、前記混合物を加熱して前記混合物から水を共沸蒸留させ、それによって式Ｖのイミン化合物を生成させるステップと、
（ｉｉｉ）ステップ（ｉｉ）で調製された式Ｖのジエン−イミン（ｄｉｅｎｅ−ｉｍｉｎｅ）化合物を還元して対応する式ＶＩａ、

のジエン−イミン化合物を得て、それを、対応する式ＶＩ、

の塩化合物、［５（Ｒ）−［［［１（Ｓ）−［［１（Ｒ）−［３，５−ビス（トリフルオロメチル）−フェニル］エトキシ］−メチル］−１−フェニル−２−プロペニル］アミノ］メチル］−５−エテニル−２−ピロリジノン］［塩２］に変換するステップであって、ここで、「塩２」は、式ＶＩの前記化合物中の塩基性官能基に結合し、そこで配位しているアニオン部分と会合している少なくとも１つのプロトンを表す、ステップとを含む、項目１から１４のいずれかに記載のプロセス。
（項目１６）
式ＩＩＩの前記化合物が、式ＩＩ、

の化合物を塩基で処理することによって提供される、項目１から１５のいずれかに記載のプロセス。
（項目１７）
式ＩＶの前記化合物が、スキーム２、

の中に図示されているプロセスによって提供され、
前記プロセスが、
ステップ２−１：
ＰｈＣＨ（ＯＣＨ_３）_２により示される２−フェニルグリシン誘導体を環化して式ＩＸのオキサゾリジノンを得るステップであって、式中、Ｃｂｚは、カルボキシベンジル−アミン保護基である、ステップ、
ステップ２−２：
式ＩＸの前記化合物を、［３，５−ビス（トリフルオロメチル）フェニル］−エトキシ−ブロモメチルエーテルと組み合わせて式Ｘのラクトンを得るステップ、
ステップ２−３：
式Ｘの前記ラクトンを還元して式ＸＩのラクトールにするステップ、
ステップ２−４：
式ＸＩの前記ラクトールを開環して式ＸＩＩのアルデヒドを得るステップ、
ステップ２−５：
式ＸＩＩの前記アルデヒドを式ＸＩＩＩのアルケニルアミンに変換するステップ、およびステップ２−６：
式ＸＩＩＩの前記アルケニルアミンを脱保護し、かくして得られた対応する遊離塩基を式ＩＶの塩に変換するステップ
を含む、項目１から１６のいずれかに記載のプロセス。
（項目１８）
式ＩＩの前記化合物が、スキームＩＩＩ

の中に図示されているプロセスに従って提供され、
前記プロセスが、
ステップ３−１：
ピログルタミン酸をトリメチルアセトアルデヒドおよびメタンスルホン酸により処理して式ＸＩＶの（３Ｒ，６Ｓ）−３−ｔｅｒｔ−ブチルジヒドロ−１Ｈ−ピロロ［１，２−ｃ］［１，３］オキサゾール−１，５（６Ｈ）−ジオンを得るステップ、
ステップ３−２：
式ＸＩＶのピロロ［１，２−ｃ］［１，３］オキサゾール−１，５（６Ｈ）−ジオンをギ酸メチルと反応させて式ＸＶのピロロ［１，２−ｃ］オキサゾール−７ａ−カルバルデヒドを得るステップ、
ステップ３−３：
式ＸＶの前記カルバルデヒドを式ＸＶＩの７ａ−ビニル−ジヒドロ−ピロロ［１，２−ｃ］［１，３］オキサゾール−１，５−ジオンに変換するステップ、および
ステップ３−４：
式ＸＶＩの前記ジオンを還元して式ＩＩの（３Ｒ）−１，１−ジメチル−７ａ（Ｒ）−エテニル−テトラヒドロ−１（Ｒ／Ｓ）−ヒドロキシ−３Ｈ，５Ｈ＝ピロロ［１，２−ｃ］オキサゾール−５−オンを得るステップ
を含む、項目１から１６のいずれかに記載のプロセス。
（項目１９）
ステップ「ｃ」が、
（ｉ）ステップ（ｂ）からの式ＶＩＩの前記化合物を、それを塩基により処理することによって式ＶＩＩｂの対応する遊離塩基に変換するステップ、および
（ｉｉ）式ＶＩＩｂの前記遊離塩基を還元して式ＶＩＩＩａ、

の化合物を得るステップを含むプロセスによって場合によって置き換えられる、項目１に記載のプロセス。
（項目２０）
ステップ「ｃ」が、式ＶＩＩの前記塩化合物を、対応する遊離塩基中間体を提供することなく、直接還元剤により処理することによって行われる、項目１に記載のプロセス。
（項目２１）
以下の式：

の化合物。 In some embodiments, preferably the reducing reagent includes (i) one or more inorganic salt compounds, such as Na ₂ S ₂ O ₅ , Na ₂ SO ₃ , or NaH ₂ PO ₃ , (ii) Phosphorous acid, such as H ₃ PO ₂ , (iii) one or more metal hydride compounds, such as sodium hydride, sodium borohydride, or lithium aluminum hydride, (iv) hydrogen and a catalyst, such as palladium Reduction with carbon, (v) an organic reducing reagent such as ascorbic acid or oxalic acid, (vi) hydrogen peroxide, or (vii) one or more metal reducing reagents such as copper, zinc, iron or Magnesium is used. Although Scheme 4 is shown with a metathesis catalyst of formula XXa, it will be appreciated that the process provides similar results and advantages when used in the presence of any metathesis catalyst.
For example, the present invention provides the following items.
(Item 1)
Formula VIIIa:

A process for producing a compound of
The process is
(A) Formula VIa:

Is cyclized in the presence of a ring-closing metathesis catalyst and optionally in the presence of an additional acid, whereby the compound of formula VIIb,

Forming a corresponding diazaspirodecene-one compound of:
(B) converting the compound of formula VIIb from step "a" to formula VII,

Converting to a salt compound of formula VII and providing said salt compound of formula VII to step (c), wherein “salt 3” of said formula is attached to a basic functional group in said compound of formula VII Representing at least one proton bound to and associated with the anion moiety coordinated therewith, and
(C) reducing said compound of formula VII from step (b) to formula VIII,

Obtaining a compound of:
(D) optionally precipitating the HCl salt of the compound of formula VIIIa to give formula VIII,

And optionally recrystallizing the precipitated salt form to give a compound of formula Ia,

Obtaining a compound of:
(Item 2)
Process according to item 1, wherein step (a) is performed in the presence of up to 2 equivalents of additional 4-methylbenzenesulfonic acid monohydrate.
(Item 3)
After step (a) and before step (b), (i) contacting the reaction mixture with an aqueous phase containing a reducing reagent under conditions suitable to reduce the metathesis catalyst; ii) The process according to any of items 1 or 2, further comprising a reduction step comprising separating the reaction mixture from the aqueous phase and any precipitate formed during the reduction step (i).
(Item 4)
4. The process of item 3, wherein the aqueous phase of part (i) of the reduction step further comprises a phase transfer catalyst.
(Item 5)
Item 5. The process according to Item 4, wherein the phase transfer catalyst is a quaternary ammonium salt.
(Item 6)
6. The process according to any of items 1 to 5, wherein the ring-closing metathesis catalyst comprises a Group 8 transition metal or a Group 6 transition metal and a carbene ligand.
(Item 7)
The metathesis catalyst is
(I) Formula XXa,

A catalyst of the formula:
The dotted line represents any bond,
Ar is phenyl, 2,4,6-trimethylphenyl, or 2,6-dimethylphenyl;
L ² is a phosphine ligand when not bound to R ³ (the semicircle dotted line between L ² and R ³ indicates any bond), and between L ² and R ³ When bound to R ³ as indicated by the dotted line of any bond in the semicircle, L ² forms a bidentate ligand with R ³ and L ² represents a further substituent. An oxygen moiety with or without, a phosphorous moiety, or a nitrogen moiety;
R ¹ is independently selected from aryl, alkyl, or hydrogen;
R ³ is an alkyl moiety or aryl moiety, or, when R ³ is not bonded to L ^2, R ³ is an alkyl moiety, an aryl moiety or a hydrogen atom,
(X) is a conjugate base of a strong acid,
M is ruthenium, palladium, or iridium.
catalyst,
(Ii) Formula XX,

A catalyst of the formula:
The metal (M) is ruthenium, palladium, iridium, or molybdenum;
(L) is (i) a phosphine ligand or (ii) a chelating ligand;
X is a conjugate base of a strong acid,
R ¹ and R ² are each independently H, phenyl, halogen or alkyl.
A catalyst, or (iii) Formula XXd,

A catalyst of the formula:
The dotted line represents any double bond,
(M) is molybdenum, ruthenium, palladium or iridium;
R ¹ is independently aryl, alkyl, or hydrogen;
Ar is aryl or benzyl,
X is a halogen moiety or a sulfonate moiety,
Item 7. The process according to Item 6, which is a catalyst.
(Item 8)
Said metathesis catalyst is of formula XXd1:

8. The process of item 7, wherein “Mes” is a 2,4,6-trimethylphenyl moiety.
(Item 9)
Said metathesis catalyst is of the formula XXd2:

7. The process of item 6, wherein “Mes” is a 2,4,6-trimethylphenyl moiety.
(Item 10)
Said metathesis catalyst is of formula XXd3:

10. The process of item 9, wherein “Mes” is a 2,4,6-trimethylphenyl moiety.
(Item 11)
Said metathesis catalyst has the formula XXd4:

The process according to item 9, wherein the compound is:
(Item 12)
The reducing reagent used after step (a) is one of (i) Na ₂ S ₂ O ₅ , Na ₂ SO ₃ , NaSO ₃ H, NaOC (O) H, or NaH ₂ PO _3. Or (ii) one or more of (ii) phosphorous acid, (iii) sodium hydride, sodium borohydride, or lithium aluminum hydride, (iv) reduction performed with hydrogen and a metal hydrogenation catalyst, 12. The process according to any of items 2 to 11, which is (v) ascorbic acid or oxalic acid, (vi) hydrogen peroxide, or (vii) one or more of copper, zinc, iron or magnesium metal. .
(Item 13)
The reducing reagent is sodium metabisulfite (Na ₂ S ₂ O ₅ ), sodium sulfite (Na ₂ SO ₃ ), sodium bisulfite (NaHSO ₃ ), sodium formate (NaOC (O) H), hypophosphorous acid ( phosphinic _acid, H 3 _PO 2), or phosphorous acid sodium salt _(NaH 2 _PO 3), or a mixture of two or more thereof the process of claim 12.
(Item 14)
A phase transfer catalyst is included in the metathesis reduction step, and the phase transfer catalyst has the formula (CH ₃ (CH ₂ ) ₃ ) ₄ N ⁺ X ⁻ , wherein “X ⁻ ” is Cl ⁻ , Br ⁻ , F ⁻ , I ^— HSO ₄ ⁻ , or a half equivalent of (SO ₄ ⁻² ).
(Item 15)
The compound of formula VI is represented by Scheme Aa:

Provided by the process illustrated in
Where the process is
(I) providing a free base compound of formula III in a water miscible solvent in the presence of a tertiary amine;
(Ii) mixing the solution from step (i) with a free base compound of formula IV and heating the mixture to azeotropically distill water from the mixture, thereby producing an imine compound of formula V;
(Iii) reducing the diene-imine compound of formula V prepared in step (ii) to the corresponding formula VIa;

Of the diene-imine compound of the formula VI

[5 (R)-[[[1 (S)-[[1 (R)-[3,5-bis (trifluoromethyl) -phenyl] ethoxy] -methyl] -1-phenyl-2 -Propenyl] amino] methyl] -5-ethenyl-2-pyrrolidinone] [salt 2], wherein "salt 2" is attached to a basic functional group in said compound of formula VI And wherein the process represents at least one proton associated with an anion moiety coordinated therewith.
(Item 16)
Said compound of formula III is of formula II,

The process according to any of items 1 to 15, which is provided by treating a compound of
(Item 17)
Said compound of formula IV is represented by Scheme 2,

Provided by the process illustrated in
The process is
Step 2-1
Cyclizing a 2-phenylglycine derivative represented by PhCH (OCH ₃ ) ₂ to give an oxazolidinone of formula IX, wherein Cbz is a carboxybenzyl-amine protecting group,
Step 2-2:
Combining said compound of formula IX with [3,5-bis (trifluoromethyl) phenyl] -ethoxy-bromomethyl ether to give a lactone of formula X;
Step 2-3:
Reducing said lactone of formula X to lactol of formula XI;
Step 2-4:
Ring opening the lactol of formula XI to obtain an aldehyde of formula XII;
Step 2-5:
Converting said aldehyde of formula XII to an alkenylamine of formula XIII, and steps 2-6:
17. Process according to any of items 1 to 16, comprising deprotecting said alkenylamine of formula XIII and converting the corresponding free base thus obtained into a salt of formula IV.
(Item 18)
Said compound of formula II is represented by Scheme III

Provided according to the process illustrated in
The process is
Step 3-1
Pyroglutamic acid was treated with trimethylacetaldehyde and methanesulfonic acid to give (3R, 6S) -3-tert-butyldihydro-1H-pyrrolo [1,2-c] [1,3] oxazole-1,5 (formula XIV 6H) -dione,
Step 3-2:
A pyrrolo [1,2-c] oxazole-7a-carbaldehyde of formula XV is reacted with methyl formate by reacting pyrrolo [1,2-c] [1,3] oxazole-1,5 (6H) -dione of formula XIV. Get the steps,
Step 3-3:
Converting said carbaldehyde of formula XV to 7a-vinyl-dihydro-pyrrolo [1,2-c] [1,3] oxazole-1,5-dione of formula XVI, and step 3-4:
Reduction of the dione of formula XVI to (3R) -1,1-dimethyl-7a (R) -ethenyl-tetrahydro-1 (R / S) -hydroxy-3H, 5H = pyrrolo [1,2- c] The process according to any of items 1 to 16, comprising the step of obtaining oxazol-5-one.
(Item 19)
Step “c”
(I) converting the compound of formula VII from step (b) to the corresponding free base of formula VIIb by treating it with a base; and (ii) reducing the free base of formula VIIb Formula VIIIa,

A process according to item 1, optionally replaced by a process comprising a step of obtaining a compound of:
(Item 20)
Process according to item 1, wherein step “c” is carried out by treating the salt compound of formula VII directly with a reducing agent without providing the corresponding free base intermediate.
(Item 21)
The following formula:

Compound.

  Other aspects and advantages of the present invention will become apparent from the following detailed description.

  A previous process for preparing a compound of formula I involves the preparation of a piperidinyl moiety followed by a reaction to add a spiropyrrolidinyl ring, while the presently claimed process is 3,5- Bis (trifluoromethyl) phenyl] ethoxy] methyl] -1-phenyl-2-propenyl] amino] methyl] -5-ethenyl-2-pyrrolidinone is cyclized. Compared to previous procedures, the present invention is convergent and shorter for preparing compounds of formula I, providing improved enantiomeric and diastereomeric selectivity and higher yields. The compounds are easier to provide and use and more cost effective.

  The terms used in the general schemes, examples, and throughout the specification include the following abbreviations, except where otherwise defined at the time they are used: Listed with their meanings. Me (methyl), Bu (butyl), t-Bu (tertiary butyl), Cbz- (carboxybenzyl), Et (ethyl), Ac (acetyl), t-Boc or t-BOC (t-butoxycarbonyl) , DMF (dimethylformamide), THF (tetrahydrofuran), DIPEA (diisopropylethylamine), RT (room temperature, roughly 25 ° C.), TFA (trifluoroacetic acid), TEA (triethylamine), NMP (1-methyl-2-pyrrolidinone) ), MTBE or TBME (tert-butyl methyl ether), Me (methyl), Mes (mesityl, ie 2,4,6-trimethylphenyl-moiety) when used as a structural substituent, Ph (phenyl), NaHMDS (hexamethyldisilazane ilizane (sodium)), DMI (1,3-dimethyl-2-imidazolidinone), AcOH (acetic acid), LHMDS (lithium bis (trimethylsilyl) amide), TMSCI (chlorotrimethylsilane or trimethylsilyl chloride), TFAA (anhydrous trifluoro) Acetic acid), and IPA (isopropanol).

  As used herein, the following terms are understood to have the following meanings unless otherwise indicated.

  Alkyl means a straight or branched aliphatic hydrocarbon having 1 to 6 carbon atoms.

  Halogen means a halogen moiety such as fluoro, chloro, bromo or iodo.

  PTC, a phase transfer catalyst, is an agent that promotes the transfer of a reactive moiety or reaction product in one reaction mixture from one phase to another.

  A wavy line that appears on the structure and connects the functional group to the structure at the binding site

は、一般に、可能性のある異性体、例えば、（Ｒ）−および（Ｓ）−立体化学を含有する異性体の混合物またはいずれかを示す。例えば、

In general, indicates possible isomers, for example a mixture of isomers containing (R)-and (S) -stereochemistry or any. For example,

当技術分野では周知のように、結合の端末側の終端に描かれていない部分の特定の原子から伸びている結合は、別なふうに記載されていない限りはその結合を介してその原子に結合しているメチル基を示している。例えば、

As is well known in the art, a bond extending from a particular atom in a portion not drawn at the terminal end of the bond is attached to that atom through that bond unless otherwise stated. The bonded methyl group is shown. For example,

しかし、本明細書の実施例においては時々、ＣＨ_３部分は、構造中にはっきりと含まれる。本明細書で用いられる場合、メチル基を表現することに対するどちらの慣習の使用も同等であることが意図されており、その慣習は、本明細書では、慣習的に理解されているようにいずれの表現についてもそれによって意味を変えることを意図することなく、便宜上互換的に使用されている。

However, sometimes in the examples herein, the CH ₃ moiety is clearly included in the structure. As used herein, the use of either convention for representing a methyl group is intended to be equivalent, and that convention is any and as conventionally understood herein. The expression is also used interchangeably for the sake of convenience without intending to change its meaning.

  The term “isolated” or “isolated form” for a compound refers to the physical state of the compound after being isolated from the process. The term "purified" or "purified form" for a compound means that it is of sufficient purity as described herein or capable of being characterized by standard analytical techniques well known to the skilled artisan. It refers to the physical state of the compound after it has been obtained from a purification process or a process described herein or known to the skilled artisan.

  In the reaction scheme representing the invention, the brackets around the structure indicate that the compound is not necessarily purified or isolated at that stage, but is preferably used directly in the next step. . Also, the various steps in the general reaction scheme do not specify separation or purification procedures for isolating the desired product, but those skilled in the art will recognize that well-known procedures are used. Will do.

  Standard parameters for the process described in Scheme 1 are discussed below.

  With respect to Scheme I above, in some embodiments, Step 1 is typically performed according to the following reaction scheme:

いくつかの実施形態において、式ＩＩＩの化合物は、ステップ１ａを行うことによって提供するのが好ましく、その場合、式ＩＩの化合物は、水と混和性である溶媒、例えば低級アルコール（すなわち、約１乃至約６個の炭素原子を有する）、例えばエタノール、メタノール、イソプロパノール、ブタノールまたはそれらの混合物中の塩基、例えば低級アルキルアミン、例えば第三級アミン、例えばトリエチルアミン、ジイソプロピルエチルアミン、またはトリブチルアミンにより、約０℃乃至約８０℃、好ましくは約１０℃乃至約６０℃、より好ましくは約２０℃乃至約３０℃の温度で、約３時間乃至約１０時間にわたって処理することによって式ＩＩＩの化合物に変換する。

In some embodiments, the compound of formula III is preferably provided by performing step 1a, wherein the compound of formula II is a solvent miscible with water, such as a lower alcohol (ie, about 1 To about 6 carbon atoms), for example, with bases such as ethanol, methanol, isopropanol, butanol or mixtures thereof, such as lower alkyl amines such as tertiary amines such as triethylamine, diisopropylethylamine, or tributylamine. Conversion to a compound of formula III by treatment at a temperature of 0 ° C. to about 80 ° C., preferably about 10 ° C. to about 60 ° C., more preferably about 20 ° C. to about 30 ° C. for about 3 hours to about 10 hours. .

  In step 1b, the compound of formula III, for example as a mixture from step 1a, is added to a solution of the free base of formula IV and heated so that the two react. After the addition, the mixture is heated to reflux, and water generated in the reaction is removed by azeotropic distillation to drive the reaction. In some embodiments, the free base of formula IV is obtained by reacting a salt of formula IVa with a water-soluble base, such as a low polarity solvent, such as toluene or a nonpolar solvent, such as xylene, or NaOH mixed in the two. Prepared from the salt of formula IVa by treatment.

  In some embodiments, in step 1c, preferably the product of step 1b is added to a hydride source, such as a metal hydride reducing reagent, such as sodium borohydride, sodium cyanoborohydride, or trihydride. Reduction with sodium acetoxyborohydride in the presence of an acid such as acetic acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid or trifluoromethanesulfonic acid and mixtures thereof provides the free base of formula VI. In some embodiments, preferably the reaction is performed in toluene, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, or a mixture of two or more thereof. In some embodiments, preferably the reaction is performed at a temperature of about 0 ° C. to about 80 ° C., preferably about 10 ° C. to about 60 ° C., more preferably about 15 ° C. to about 25 ° C. In some embodiments, preferably the reaction is performed for about 2 hours to about 10 hours. After obtaining the free base of formula VI, it is converted to a salt compound of formula VIa by treatment with an acid reagent such as p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, HCl, HBr, or sulfuric acid. (Step 1c ′). In some embodiments, preferably the conversion to a salt compound of formula VIa is carried out by using a water miscible solvent, such as an alkyl alcohol having about 1 to about 6 carbon atoms, such as methanol, ethanol, propanol. , Isopropanol, or butanol and its isomers, or a mixture of two or more thereof, after which the salt product is isolated.

  In step 2, the salt compound of formula VIa is converted to the free base, which is then cyclized using a ring-closing metathesis catalyst and the resulting product is again converted to a salt and isolated.

  The ring-closing metathesis catalyst is preferably one containing a metal with a carbene ligand, for example a catalyst of formula XX:

式中、金属（Ｍ）は、好ましくは、８個の「ｄ」軌道電子を提供しているホルマール酸化状態の遷移金属（８族遷移金属、例えば、ルテニウム、パラジウムまたはイリジウム）、あるいは６族遷移金属、例えば、モリブデンであり、（Ｘ）は、強酸の共役塩基であり、好ましくは、Ｘは、スルホネート部分、例えば、トシレートであるか、またはハロゲン部分、例えば、クロリドであり、（Ｌ^１）は、かなりのπ逆供与能を有するσ結合した炭素配位子、例えば、式ＸＸａの触媒中に示されているように、イミダゾリジン配位子

Wherein the metal (M) is preferably a transition metal in a formal oxidation state (group 8 transition metal, eg ruthenium, palladium or iridium) or group 6 transition providing 8 “d” orbital electrons. A metal, such as molybdenum, and (X) is a conjugate base of a strong acid, preferably X is a sulfonate moiety, such as tosylate, or a halogen moiety, such as chloride, (L ¹ ) Is a sigma-bonded carbon ligand with significant π-reverse donating ability, such as an imidazolidine ligand as shown in the catalyst of formula XXa

（ただし、Ａｒは、アリール部分、例えば、ベンジル、フェニルまたはメシチル（２，４，６−トリメチルフェニル）部分）であり、Ｌ^２は、ホスフィン配位子、例えば（Ｃｙ_３Ｐ）であるか、または図のように、Ｌ^２は、Ｌ^２とＲ^３との間の半円の点線によって示されているように、場合によって、Ｒ^３に結合しており、Ｌ^２が、Ｒ^３を介してカルベン部分に結合しているときは、Ｌ^２は、二座配位子を形成し、Ｌ^２は、キレート化部分、例えば、酸素部分、亜リン酸部分、または窒素部分、例えば、式ＸＸｄの触媒中に示されているイソプロポキシ−ベンジリデン二座配位子中の酸素部分であり、Ｒ^１は、アリール、アルキル、または水素から独立して選択され、Ｒ^３は、アルキルまたはフェニル部分であるか、またはＲ^３が、Ｌ^２に結合していないときは、Ｒ^３は、水素であり得る。

Where Ar is an aryl moiety, such as a benzyl, phenyl or mesityl (2,4,6-trimethylphenyl) moiety, and L ² is a phosphine ligand, such as (Cy ₃ P), or as shown in FIG, ^{L 2,} as indicated by the dotted semicircle between ^{L 2} and ^{R 3,} optionally, it is linked to ^{R 3, L 2} is, via the ^{R 3} When bound to a carbene moiety, L ² forms a bidentate ligand and L ² is a chelating moiety, eg, an oxygen moiety, a phosphite moiety, or a nitrogen moiety, eg, formula XXd The oxygen moiety in the isopropoxy-benzylidene bidentate ligand shown in the catalyst of R ¹ is independently selected from aryl, alkyl, or hydrogen, and R ³ is an alkyl or phenyl moiety there is, or ^{R 3} When not bound to L ² is, R ³ may be hydrogen.

Suitable ring closing metathesis catalysts are commercially available and include, for example: (I) US Pat. No. 6,215,019 states that “Grubbs' first generation catalyst (Grubbs ′
Catalysts described as "First generation catalyst" and those described as "Grubbs' Second Generation Catalysts" in WO 99/51344 and WO 00/71554 International Publication No. PCT / US01 / 24955 is described as "Hoveyda-Grubbs' First and Second Generation catalysts", both of which are available from Materia ii) Zhan's catalyst described in WO 2007/003135 and available from Zannan Pharma And (iii) Grela's catalyst described in International Publication No. WO 2004/035596 and available from Boehringer-lngelheim. In some embodiments of the invention, a catalyst having (i) a chelated isopropoxybenzylidene ligand and (ii) a bismestiylene substituted N-heterocyclic carbene ligand, such as Hoveyda-Grubbs It is preferred to use a second generation catalyst.

  In some embodiments, preferably the formula:

の触媒を使用する。

The catalyst is used.

  In some embodiments, preferably the formula:

の触媒（式中、Ｒ^４は、「Ｈ−」、ニトロ部分（−ＮＯ_２）、またはスルホンアミド部分（−ＳＯ_２Ｎ（Ｒ^５）_２であり、ここで、Ｒ^５は、１０個以下の炭素原子のアルキル部分である）を使用する。

(Wherein R ⁴ is “H—”, a nitro moiety (—NO ₂ ), or a sulfonamide moiety (—SO ₂ N (R ⁵ ) ₂ ), wherein R ⁵ is 10 or less. Is the alkyl portion of the carbon atom.

  With respect to Scheme 1, Step 2, in some embodiments, the reaction mixture usage of the ring-closing metathesis catalyst (catalyst usage) is about 100 relative to the amount of the compound of Formula V initially present in the reaction mixture. It is preferred to use in an amount of from mol% to about 0.1 mol%, more preferably the catalyst is in an amount of from about 20 mol% to 0.1 mol%, more preferably from about 10 mol% to about 0.00 mol. Used in an amount of 5 mol%. As described above, the addition of an acid in step 2, such as 4-methylbenzenesulfonic acid monohydrate or toluenesulfonic acid, to the reaction mixture is complete or nearly complete under the given reaction conditions. The amount of reaction mixture catalyst required to achieve this conversion can be reduced. Table 1 below shows the results obtained by adding various amounts of p-toluenesulfonic acid to the reaction mixture and observing the amount of substrate conversion as a function of catalyst usage with and without added acid. It is clear. In some embodiments where acid is added to reduce catalyst usage, the acid is preferably about 0.01 equivalents to about 2 equivalents relative to the amount of substrate initially present in the reaction mixture. More preferably, the acid is added in an amount of about 0.1 to 1.8 equivalents, more preferably the acid is about 0.2 equivalents relative to the amount of substrate initially present in the reaction mixture. Add in an amount of up to 1.5 equivalents.

  While not wishing to be bound by theory, we have found that the best results regarding the use of the acid added in step 2 to reduce catalyst usage are the calculated pKa of Intermediate IV, pKa ≦ It is believed to be achieved by adding an acid possessing 6.5 to the reaction mixture. In order to reduce the catalyst loading required to achieve high substrate conversion, various types of acids such as, but not limited to, (i) mineral acids such as HCl, HBr , HI, phosphoric acid or sulfuric acid or mixtures thereof, and (ii) organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-nitrobenzene Sulfonic acids, halogen-substituted benzene sulfonic acids, or heterocyclic aromatic sulfonic acids, or mixtures thereof are considered useful.

表Ｉに関して、スキームＩ（上記）のステップ２に従う環化反応は、環化すべき基質の量に対して０乃至約２モル当量の添加酸を用いて行った。これらのデータは、ステップ２において反応混合物に酸を添加することによって基質の高率の変換を達成するために反応混合物中に必要な触媒使用量を、４．５倍を超えて減少することができることを示している。それ故、添加酸無しで１００％近くの基質変換を達成するためには７モル％以上の使用量が必要であったところが、反応混合物中で１５０モル％の追加の酸と併用して１．０モル％の触媒使用量を用いることにより１００％に近づく基質の変換を達成することができた。

With respect to Table I, the cyclization reaction according to Step 2 of Scheme I (above) was performed using 0 to about 2 molar equivalents of added acid relative to the amount of substrate to be cyclized. These data show that by adding acid to the reaction mixture in step 2, the catalyst usage required in the reaction mixture to achieve a high conversion of substrate is reduced by more than 4.5 times. It shows what you can do. Therefore, in order to achieve near 100% substrate conversion without added acid, a use amount of 7 mol% or more was necessary, but in combination with 150 mol% additional acid in the reaction mixture. Substrate conversion approaching 100% could be achieved by using 0 mole% catalyst loading.

In some embodiments, the ring closure reaction of Step 2 can be performed by using a non-coordinating medium polarity solvent such as toluene, trifluorotoluene, chlorobenzene, benzene, xylene (s), chloroform, dichloromethane, or dichloroethane. Preferably, the reaction is carried out in an anhydrous, degassed (eg, using N ₂ ) reaction medium. In general, the reaction is carried out at or slightly above atmospheric pressure. In some embodiments, the ring-closing metathesis reaction involves dissolving the catalyst in a solvent that is the same as or similar to the reaction solvent, and slowly adding the catalyst solution over a period of about 30 minutes, It is preferred to carry out the reaction by maintaining the temperature of the reaction mixture within a temperature range of about 20 ° C to about 100 ° C, preferably about 30 ° C to 90 ° C, more preferably about 60 ° C to about 80 ° C.

  In some embodiments, it is preferred to remove the metal from the catalyst at the end of the cyclization reaction using the process described in Scheme 4, ie, the product of the ring closure treatment is treated with an aqueous solution of a reducing reagent. Then, the obtained metal species is extracted into the aqueous layer. Suitable reducing reagents include, but are not limited to, inorganic reagents such as sodium bisulfite, sodium metabisulfite, sodium thiosulfite, sodium formate, sodium borohydride and derivatives thereof.

In some embodiments using the process of Scheme 4 to remove metal from the metathesis catalyst, a phase transfer catalyst (PTC) is also present in the reaction mixture, about 0.05 to the amount of reducing reagent used. It is preferred to use about 200 mol% PTC to mol% PTC to the amount of reducing reagent used, preferably PTC is about 0.1 mol% to the amount of reducing reagent used. Used in an amount that is from about 100 mole percent. Suitable phase transfer catalysts for use in the process, the formula _{^{(R * 4 N + X -}} ) is an alkyl group wherein "R ^*" is defined herein, "X ”Is an anion, and preferably includes, but is not limited to, quaternary ammonium salts in which“ X ”is Cl ⁻ , Br ⁻ , I ⁻ , F ⁻ , or NO ₃ ^— . The inventors surprisingly found that when the process is carried out in the presence of a suitable phase transfer catalyst, the PTC is reduced at a lower temperature, for example as low as 25 ° C., for example 1 Allows progress to completion in less than less time, or achieves complete reduction in the absence of phase transfer catalyst in both reaction time and reaction temperature, depending on the temperature range selected We found that it can be reduced beyond what it takes to do.

In some embodiments, the cyclized product from which the catalyst has been removed is obtained by reacting the reaction mixture containing the cyclized product with (i) a mineral acid such as HCl, HBr, HI, H ₃ PO ₄ , Or H ₂ SO ₄ , (ii) organic acids or substituted organic acids such as maleic acid, fumaric acid, tartaric acid or trifluoroacetic acid, (iii) sulfonic acid or substituted sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid , Benzenesulfonic acid, p-toluenesulfonic acid, or p-nitrobenzenesulfonic acid is preferably converted to a salt by treatment with a reagent. In some embodiments, it is preferred to prepare the HCl salt of the compound of formula VI.

  With respect to Scheme I, the salt of Formula VII is converted to the free base form in Step 3. In some embodiments, the transformation converts a compound of formula VII to a base, such as NaOH, KOH, NaOR, where “R” is an alkyl group containing from about 1 to about 12 carbon atoms. It is preferable to achieve this by processing. In some embodiments, the conversion of the compound of Formula VII in Step 3 is performed in a reaction solvent comprising a low polarity organic solvent, such as toluene, xylene, ether (eg, diethyl ether and methyl t-butyl ether). The free base of VII is obtained, and then the free base is hydrogenated by hydrogenation, for example, in the presence of a hydrogenation catalyst such as a palladium carbon, platinum carbon, palladium oxide, ruthenium, or Wilkinson catalyst, or mixtures thereof. To give the compound of formula VIII. In some embodiments, Step 3 comprises a low polarity organic solvent, such as toluene or xylene, or a polar organic solvent, such as an alcohol (C1-C12 linear or branched alkyl), or ether, or water, Or preferably in a mixture of two or more thereof. In some embodiments, after the hydrogenation reduction is complete, the catalyst used in Step 3 is removed from the reaction mixture, for example, by filtration, and the product compound in the reaction mixture is then In embodiments where the acid is treated to the corresponding salt, eg, the product compound is treated with HCl in this step, the compound of formula VIII (Scheme I) is obtained as the hydrochloride hydrate.

  The inventors have surprisingly found that, in connection with Scheme I above, the tetrahydropyridine salt compound of formula VII can be directly reduced to give the corresponding amine salt compound. When the compound of formula VII is the hydrochloride salt, the reduction of the salt compound of formula VII does not require the formation of the intermediate free base form of tetrahydropyridine, ie the compound of formula VIIb, without hydrochloric acid of formula VIII. Produces salt hydrate compounds directly. In some embodiments using direct reduction of the tetrahydropyridine salt compound of formula VII, preferably after the reduction reaction is complete, the catalyst used in the reduction is removed from the reaction mixture by mechanical means such as, for example, Removed by filtration and the resulting amine salt is recovered from the filtrate.

  In order to carry out the reduction of the salt compound of formula VII directly without first providing the free salt form of tetrahydropyridine, the inventors have surprisingly found that the reaction comprises (i) a low polarity organic solvent. E.g. toluene or xylene or mixtures thereof; (ii) polar organic solvents, e.g. alcohols containing from about 1 carbon atom to about 12 carbon atoms, or mixtures of two or more thereof; (iii) about It has been found that it is preferably carried out in a solvent that is an organic ether containing from 2 to about 12 carbon atoms or a mixture of two or more thereof, and (iv) water, or any two or more mixtures thereof. .

  Suitable methods for reducing a salt form of a tetrahydropyridine compound to the corresponding cyclohexylamine include treatment of the compound of formula VII with hydrogen in the presence of a hydrogenation catalyst. Suitable hydrogenation catalysts include, for example, palladium carbon, palladium oxide, platinum carbon, ruthenium and Wilkinson catalysts or mixtures of two or more thereof.

  In some embodiments, following step 3 of Scheme I, preferably the step 3 product is recrystallized from an alcohol / water solution thereby providing the desired crystalline form of the compound of formula Ia. Do. Suitable alcohol solvents useful for performing step 4 include, but are not limited to, alcohols having from about 1 to about 12 carbon atoms or mixtures of two or more thereof. Alternatively, for recrystallization, the compound of formula VIII is suspended in toluene and the suspension is extracted with aqueous NaOH and then treated with HCl to precipitate the compound of formula Ia.

  As noted above, in some embodiments of the present invention, it is preferred to prepare the intermediate of formula IV using the process illustrated in Scheme 2. In some embodiments employing the process of Scheme 2 to provide compounds of Formula IV, it is preferred to use the conditions and parameters shown in Scheme 2ab below in the implementation of Scheme 2.

スキーム２ａｂのプロセスにおける、ステップ２−１〜２−３は、上記の米国特許第７，０４９，３２０号（’３２０号特許）実施例、４３〜４４段、化合物１〜３に記載されており、スキーム２ａｂに示されているステップ２−５．１を実施することに由来するトリフェニルホスフィンオキシドの除去は、欧州特許出願公開第ＥＰ０８５０９０２号の４〜５頁に記載されている。

Steps 2-1 to 2-3 in the process of Scheme 2ab are described in the above-mentioned US Pat. No. 7,049,320 ('320 patent) example, 43-44, compounds 1-3. The removal of triphenylphosphine oxide resulting from carrying out Step 2-5.1 shown in Scheme 2ab is described on pages 4-5 of EP 0850902.

In some embodiments, steps 2-4 of Scheme 2ab are performed using a base such as KHCO ₃ or NaHCO ₃ in a solvent such as NMP water, a mixture of acetonitrile and water, or a mixture of acetone and water. Is preferred. In some embodiments, preferably the reaction mixture is a mixture of about 0 ° C. to about 60 ° C., preferably about 5 ° C. to about 50 ° C., more preferably 15 ° C. to about 25 ° C. Stirring while maintaining temperature, and after stirring for a period of time, heat the reaction mixture to a temperature of up to about 90 ° C., preferably less than about 70 ° C., more preferably about 45 ° C. to about 55 ° C. The reaction mixture is then cooled to ambient temperature (generally about 25 ° C.) and the reaction mixture at ambient temperature is cooled to an organic solvent such as methyl t-butyl ether (MTBE), ethyl acetate, isopropyl acetate, toluene. Extract with xylene or a mixture of two or more thereof.

Further related to Scheme 2ab, Step 2-5 converts the product of Step 2-4 to Ph ₃ PCH ₃ X (X═Cl, Br, or I in an organic solvent such as toluene, THF, MTBE. ) And hexamethyldisilazane sodium or lithium, or a mixture of lithium diisopropylamide, sodium or potassium alkoxide at a temperature range of -20 to 60 ° C, preferably 5 to 40 ° C, more preferably 10 to 25 ° C. By doing. The reaction mixture is warmed to room temperature and stirred, then cooled to the range of −30 to 40 ° C., preferably −20 to 30 ° C., more preferably −10 to 20 ° C., quenched with dilute acetic acid, Wash with sodium carbonate solution. Process the product MgCl _2, stirred at room temperature, then treated with silica gel. Filtration of the solid yields a compound of formula XIII.

  In Step 2-6, the crude product of Formula XIII is treated with TMSI (iodotrimethylsilane) and quenched with an alcohol having from about 1 to about 12 carbon atoms, thereby converting the free base of Formula IV. Provided (step 1b for scheme I). As shown in steps 2-6 of Scheme 2ab, the provided free base of formula IV is treated with an acid such as maleic acid, hydrochloric acid, and hydrobromic acid to form the corresponding salt. Preferably, however, maleic acid is used, thereby providing the corresponding maleate compound of formula IVa. In some embodiments, preferably the salts provided thereby are crystallized from toluene and an anti-solvent such as hexane, heptane or octane to provide a crystalline form of the salt.

  As noted above, in some embodiments of the present invention, the intermediate of formula II is preferably prepared using the process shown in Scheme 3. In some embodiments using the process of Scheme 3 to provide compounds of Formula II, it is preferred to use the conditions and parameters shown in Scheme 3ab below in Scheme 3 practice.

スキーム３ａｂに関連するいくつかの実施形態において、ステップ３−１は、いくつかの方法：
ａ）ピログルタミン酸を、ジエチレングリコールジメチルエーテル、トリメチルアセトアルデヒドおよび強酸、例えば、メタンスルホン酸と共に還流させるか、または
ｂ）ピログルタミン酸を、トリメチルアセトアルデヒドおよび強酸、例えば、メタンスルホン酸と共に加熱するか、または
ｃ）ピログルタミン酸を、ヘキサメチルジシラザン（ｄｉｓｉｌｉｚａｎｅ）と共に還流させ、次にその生成物をトリメチルアセトアルデヒドおよびメタンスルホン酸と反応させるか、または
ｄ）ピログルタミン酸およびトリエチルアミンをクロロトリメチルアミンと共に加熱し、次にその生成物をトリメチルアセトアルデヒドおよび強酸、例えば、メタンスルホン酸と反応させるか、または
ｅ）無水トリフルオロ酢酸を、ピログルタミン酸、トリメチルアセトアルデヒドおよび強酸の混合物に加え、その反応が完了するまで温度を約５０℃乃至約１００℃に維持するか
の１つを用いて実施するのが好ましい。

In some embodiments related to Scheme 3ab, step 3-1 comprises several methods:
a) refluxing pyroglutamic acid with diethylene glycol dimethyl ether, trimethylacetaldehyde and a strong acid such as methanesulfonic acid, or b) heating pyroglutamic acid with trimethylacetaldehyde and a strong acid such as methanesulfonic acid, or c) pyro Glutamic acid is refluxed with hexamethyldisilazane and the product is then reacted with trimethylacetaldehyde and methanesulfonic acid, or d) pyroglutamic acid and triethylamine are heated with chlorotrimethylamine and then the product E) with trimethylacetaldehyde and a strong acid, for example methanesulfonic acid, or e) trifluoroacetic anhydride, pyroglutamic acid, trimethyl It is preferably carried out using a mixture of tylacetaldehyde and strong acid and one of maintaining the temperature between about 50 ° C. and about 100 ° C. until the reaction is complete.

  In method (a), the compound of formula XIV is prepared by refluxing pyroglutamic acid in diethylene glycol dimethyl ether solvent in the presence of trimethylacetaldehyde and a strong acid. In some embodiments, the strong acid is preferably trifluoroacetic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or p-nitrobenzenesulfonic acid. . In some embodiments of method (a), the step of refluxing with pyroglutamic acid comprises dean for the reflux apparatus in the presence of a co-solvent such as toluene, xylene, cyclohexane, THF, or a mixture of two or more thereof. Use a Stark moisture remover until the reaction is complete at reflux temperature.

  In method (b), the mixture of pyroglutamic acid, trimethylacetaldehyde and strong acid without the diethylene glycol dimethyl ether solvent used in method (a) is heated in a device that allows moisture removal, such as a Dean Stark moisture removal device. . In method (b), as in method (a), in some embodiments, the strong acid may be trifluoroacetic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- It is preferred to select toluenesulfonic acid or p-nitrobenzenesulfonic acid. In some embodiments, the mixture is generally heated to reflux from about 100 ° C. to about 120 ° C. while water is distilled off azeotropically with a trap until reflux is complete. to continue. For bench scale devices this is typically achieved in about 14.5 hours.

  In method (c), pyroglutamic acid and hexamethyldisilazane in a solvent, preferably dioxane, diglyme, toluene or N-methylpyrrolidinone (NMP), are heated to reflux for about 6 hours to about 12 hours. . Trimethylacetaldehyde and a strong acid such as trifluoroacetic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or p-nitrobenzenesulfonic acid are added to the product and the product obtained The mixture is heated to 90 ° C. for about 4 hours to about 12 hours.

  In method (d), chlorotrimethylsilane is added to a mixture of pyroglutamic acid and triethylamine in toluene while keeping the temperature below 30 ° C., and then the mixture is heated to reflux until silylation is complete. . The resulting trimethylsilyl-protected compound is added to a solvent such as N-methyl-2-pyrrolidone or acetonitrile, trimethylacetaldehyde and a strong acid such as trifluoroacetic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, trifluoromethane. Treating with sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or p-nitrobenzenesulfonic acid, the temperature of the reaction mixture is about 50 ° C to about 100 ° C, preferably about 60 ° C to about 90 ° C, more preferably Is maintained at a temperature range of about 70 ° C. to about 85 ° C. until the reaction is complete, typically for about 18 hours to about 24 hours.

  In method (e), a mixture of pyroglutamic acid, trimethylacetaldehyde, and strong acid is provided and trifluoroacetic anhydride is added thereto. In some embodiments, the strong acid is an organic acid such as trifluoroacetic acid; a mineral acid such as phosphoric acid or sulfuric acid; a sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Selected from toluenesulfonic acid or p-nitrobenzenesulfonic acid. In some embodiments, the reaction is preferably performed in an organic solvent, such as toluene or N-methyl-pyrrolidone. In some embodiments, the reaction mixture is preferably maintained at a temperature of about 70 ° C. to about 95 ° C., more preferably the temperature is maintained at about 80 ° C. to about 95 ° C. In general, the reaction mixture is generally maintained for about 5 to about 10 hours until the reaction is completed at the desired temperature range.

In step 3-2, the compound of formula XIV is (i) a solvent, preferably 1,3-dimethyl-2-imidazolidinone (DMI) or tetrahydrofuran, (ii) methyl formate or ethyl formate, and ( iii) optionally mixed with a Lewis acid, for example CuCl or ZnCl ₂ . When a Lewis acid is used, it is generally added in an amount up to about 1 equivalent relative to the amount of compound of formula XIV used. In some embodiments, a Lewis acid is used to increase yield in this step and to simplify work up of the reaction mixture. Following the addition of the constituents, the reaction mixture is cooled to a temperature of about [−100] ° C. to about [−55] ° C., and then the reaction mixture is maintained at a temperature of lithium bismuth while maintaining the temperature of the reaction mixture. (Trimethylsilyl) amide (LiHMDS) is added followed by chlorotrimethylsilane (TMSCI). After the addition is complete, the reaction mixture is warmed to a temperature of about 0 ° C. to about [+10] ° C. and mixed with an aliquot of citric acid or acetic acid solution. The resulting intermediate is treated with trifluoroacetic acid to give pyrrolo [1,2-c] oxazole-7a-carbaldehyde of formula XV.

In step 3-3, the carbaldehyde of formula XV is converted to a methyltriphenylphosphonium halide (halide = Cl, Br (B), for example, in an organic solvent, preferably toluene, THF, or MTBE, by a Wittig reaction. Or I) and hexamethyldisilazane sodium or lithium or lithium diisopropylamide or sodium or potassium alkoxide to about [-20] ° C to about [+60] ° C, preferably about [-10] ° C to about [+30] ° C. 7a-vinyl of formula XVI by treating it in a temperature range of about [+5] ° C. to about [+15] ° C., and more preferably by quenching the reaction mixture by adding NaCl and acetic acid. -Dihydro-pyrrolo [1,2-c] [1,3] oxa It is converted into Lumpur-1,5-dione. The product is treated with MgCl _2, MgCl 2 formed thereby _- triphenylphosphine oxide complex is separated by filtration from the reaction mixture. The product remaining in the reaction mixture is crystallized from toluene and heptane to give the compound of formula XVI.

  In step 3-4, the compound of formula XVI is dissolved in an ether solvent, preferably tetrahydrofuran or MTBE, or in a low polarity organic solvent such as toluene. The reaction mixture is heated at a temperature of about [-40] ° C to about 0 ° C, preferably about [-30] ° C to about [-5] ° C, more preferably about [-25] ° C to The temperature is maintained at a temperature of about [-15] ° C., and the reaction mixture is then treated with lithium tri (t-butoxy) aluminum hydride, lithium aluminum hydride, or lithium diisobutylaluminum hydride, and the temperature is reduced to about Raise the temperature from [−10] ° C. to about [+10] ° C. over a period of about 10 hours to about 16 hours and maintain until the reaction is complete. When the reaction is complete, the reaction mixture is quenched with an acetate solvent, which is preferably ethyl acetate, methyl acetate, or isopropyl acetate, and then successively, acid, preferably glacial acetic acid or triethyl. Contacting an aliquot of fluoroacetic acid and then an aliquot of sodium sulfate decahydrate provides the compound of Formula II.

  The intermediate compounds for which patents have been filed per se are:

いくつかの実施形態において、化合物ＩＶは、水和物を含めたマレイン酸塩としてか、または水和物を含めた塩酸塩として単離するのが好ましい。いくつかの実施形態において、式ＶＩおよびＶＩＩの化合物は、好ましくは塩酸塩または４−メチル−ベンゼンスルホン酸塩として、より好ましくは４−メチル−ベンゼンスルホン酸塩の水和物として単離する。

In some embodiments, compound IV is preferably isolated as a maleate salt including a hydrate or as a hydrochloride salt including a hydrate. In some embodiments, the compounds of formula VI and VII are preferably isolated as hydrochloride or 4-methyl-benzenesulfonate, more preferably as hydrate of 4-methyl-benzenesulfonate.

  As described above, at the end of step 2 of Scheme 1, the process shown in Scheme 4 above can be used to remove the metal from the reaction mixture of the ring-closing metathesis reaction, and the metal is recycled. Product intermediate compounds that are substantially free of contamination from the metathesis catalyst.

  With respect to Scheme 4 shown hereinabove, the inventors have surprisingly discovered that when the ring closure reaction is complete, the metathesis catalyst reacts the reaction mixture containing the metathesis catalyst with the metathesis catalyst. It was found that it can be removed from the reaction mixture by treatment with a reducing reagent. The process described in Scheme 4 includes reducing the catalyst in a reaction mixture comprising a water immiscible solvent by contacting the reaction mixture with an aqueous solution containing a reducing reagent, wherein The reduction product of the metathesis catalyst is soluble in the aqueous layer and is therefore physically separated from the organic layer, for example by separation or decantation, or organically using the immiscibility of the two layers. It is insoluble in either the layer or the aqueous layer and is therefore physically separated from the reaction mixture by filtration.

Suitable reducing reagents for performing the metathesis reduction reaction described in Scheme 4 above include (i) Na ₂ S ₂ O ₅ , Na ₂ SO ₃ , NaSO ₃ H, NaOC (O) H, or NaH. One or more inorganic salt compounds which are ₂ PO ₃ , (ii) phosphorous acid, eg H ₃ PO ₂ , (iii) one or more metal hydride compounds, eg sodium hydride, borohydride Sodium, or lithium aluminum hydride, (iv) a reduction catalyst such as hydrogen in the presence of palladium on carbon, (v) organic reducing reagents such as ascorbic acid and oxalic acid, (vi) hydrogen peroxide, or (vii) ) One or more metals capable of performing a reduction reaction, such as copper, zinc, iron or magnesium.

In some embodiments, an inorganic salt compound that can function as a phase transfer catalyst (PCT) during the reaction, such as a quaternary ammonium salt, such as (CH ₃ (CH ₂ ) ₃ ) ₄ N ⁺ X ^−. (Wherein X is preferably chlorine, bromine, iodine, fluorine, bisulfuric acid (HSO ₄ ⁻ ), sulfuric acid (SO ₄ ⁻² ), or nitrate anion). The inventors have surprisingly found that the reaction can be carried out at a temperature as low as about 20 ° C. by including PCT, where a temperature of about 40 ° C. is required for the reaction to proceed without PCT. I found that I can make it possible. Moreover, the presence of PTC in the reaction can significantly reduce the time required to complete the reaction at a particular temperature, for example, a reaction that requires about 1 hour of reaction time for a particular temperature. Is reduced to about 6 minutes.

Thus, in some embodiments utilizing the reaction process of Scheme 4 to remove the metathesis catalyst used for ring closure in the synthesis, toluene, trifluoro as the water-immiscible solvent containing the reaction mixture. It is preferred to use toluene, chlorobenzene, benzene, xylene (s), dichloromethane, or dichloroethane or a mixture of two or more thereof. In some embodiments utilizing the reaction process of Scheme 4 to remove the metathesis catalyst used for ring closure in the synthesis, the reduction reaction is preferably conducted at a temperature of about 20 ° C to about 100 ° C. In some embodiments utilizing the reaction process of Scheme 4 to remove the metathesis catalyst used for ring closure in the synthesis, the reaction is preferably conducted for about 0.1 hours to about 24 hours. Generally, when this process is used to remove a metathesis catalyst, the reaction is continued until all the metathesis catalyst is reduced. At the end of the reduction reaction, the reduced metal is generally in the form of an ML ₂ complex and is soluble and therefore extracted during the reaction into an aqueous solution containing a reducing reagent, or Either it is insoluble in either the organic or aqueous layer and therefore precipitates from the organic and aqueous mixture.

In some embodiments that utilize the reaction process of Scheme 4 to remove the metathesis catalyst used for ring closure in the synthesis, when the “M” of the metathesis catalyst, eg, the metathesis catalyst of Formula XXa, is ruthenium. Preferably uses Na ₂ S ₂ O ₅ , Na ₂ SO ₃ or Pd carbon in the presence of hydrogen as a reducing reagent. In some embodiments that utilize the reaction process of Scheme 4 to remove the metathesis catalyst used for ring closure in the synthesis, when the “M” of the metathesis catalyst, eg, the metathesis catalyst of Formula XXa, is ruthenium. Preferably includes PTC as described above, and more preferably, [(CH ₃ (CH ₂ ) ₃ ) ₄ N ⁺ (HSO] as a phase transfer catalyst in a process in which “M” of the metathesis catalyst is ruthenium. ₄ ^-)] or _{[(CH 3 (CH 2)} 3) 4 N +] 2 (SO 4 -2)] preferably used.

  Of course, the novel method shown above for separating the metathesis catalyst from the reaction mixture at the end of the reaction would be performed in order to cleanly remove the metal metathesis catalyst from other reactions employing such a catalyst. As long as the reduction product containing is insoluble in the mixed phase reaction product obtained after the reduction or is soluble in the aqueous phase of the mixed phase reaction product, it can be used.

  An example illustrating the process of the invention follows. Unless otherwise specified, all reagents were commercial laboratory grade and used as received.

  (Example 1)

［（１Ｓ）−１−（｛（１Ｒ）−１−［３，５−ビス（トリフルオロメチル）フェニル］エトキシ｝メチル）−１−フェニルプロプ−２−エニル］アミンモノマレイン酸塩の調製
ステップ１：
式ＸＩの化合物（ＷＯ２００３／０５４８４０に記載されているようにして調製した）（１００．０ｇ、１５４．９ｍｍｏｌ）のＮＭＰ（２００ｍＬ）中のＲＴの溶液に、ＫＨＣＯ_３（４．６ｇ、４５．９ｍｍｏｌ）および水（３ｍＬ、１６６．７ｍｍｏｌ）を連続して加えた。得られた混合物を、２０℃で１６時間にわたって激しく撹拌した。温度を次に５０℃に上げ、その反応物をさらに２時間撹拌した。その反応物を冷却してＲＴに戻した後、２００ｍＬの水を加えた。得られた溶液を、ＴＢＭＥにより抽出した（２×２００ｍＬ）。その合わせた有機層を、１４％のＮａＨＳＯ_３および７％のＡｃＯＨの水溶液（２×１００ｍｌ）、ＮａＨＣＯ_３の飽和水溶液、およびブラインにより連続して洗浄した。その有機層を乾燥（Ｎａ_２ＳＯ_４）して、濾過し、真空中で濃縮した。式ＸＩＩの粗製化合物を、さらなる精製はしないで次の段階にそのまま持ち込んだ。

Preparation of [(1S) -1-({(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} methyl) -1-phenylprop-2-enyl] amine monomaleate 1:
To a solution of the compound of formula XI (prepared as described in WO2003 / 054840) (100.0 g, 154.9 mmol) in NMP (200 mL) at RT was added KHCO ₃ (4.6 g, 45.9 mmol). ) And water (3 mL, 166.7 mmol) were added sequentially. The resulting mixture was stirred vigorously at 20 ° C. for 16 hours. The temperature was then raised to 50 ° C. and the reaction was stirred for an additional 2 hours. The reaction was cooled to RT and 200 mL of water was added. The resulting solution was extracted with TBME (2 × 200 mL). The combined organic layers were washed sequentially with 14% aqueous NaHSO ₃ and 7% aqueous AcOH (2 × 100 ml), saturated aqueous NaHCO ₃ , and brine. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude compound of formula XII was taken directly to the next step without further purification.

ステップ２：
トルエン（２００ｍＬ）中のＰｈ_３ＰＣＨ_３Ｂｒ（７８．０ｇ、２１７．０ｍｍｏｌ）のスラリーに、ＮａＨＭＤＳ（トルエン中１３％、３０６ｇ、２１７ｍｍｏｌ）を−１５℃でゆっくり加えた。得られた混合物を１時間スラリー化させた後、ステップ１からの粗生成物をゆっくり加えた。その反応物を次にＲＴまで温め、さらに１時間撹拌した。０℃に冷却した後、その反応物を６％のＡｃＯＨ水溶液（４００ｍＬ）により失活させ、ＮａＨＣＯ_３の飽和水溶液により洗浄した。その有機層を次にＭｇＣｌ_２（２５ｇ、２６３ｍｍｏｌ）により処理し、ＲＴで３時間撹拌した。濾過後、その有機層をシリカゲル（１００ｇ）で処理し、３０分間撹拌した。濾過後、その固体をトルエンで洗浄した（２×１００ｍＬ）。その濾液を集め、真空中で濃縮してトルエン中の式ＸＩＩＩの粗生成物を生じさせ、それをさらなる精製はせずに次のステップにそのまま持ち込んだ。

Step 2:
To a slurry of Ph ₃ PCH ₃ Br (78.0 g, 217.0 mmol) in toluene (200 mL) was added NaHMDS (13% in toluene, 306 g, 217 mmol) slowly at −15 ° C. After the resulting mixture was slurried for 1 hour, the crude product from Step 1 was added slowly. The reaction was then warmed to RT and stirred for an additional hour. After cooling to 0 ° C., the reaction was quenched with 6% aqueous AcOH (400 mL) and washed with a saturated aqueous solution of NaHCO ₃ . The organic layer was then treated with MgCl ₂ (25 g, 263 mmol) and stirred at RT for 3 hours. After filtration, the organic layer was treated with silica gel (100 g) and stirred for 30 minutes. After filtration, the solid was washed with toluene (2 × 100 mL). The filtrate was collected and concentrated in vacuo to give the crude product of formula XIII in toluene, which was taken directly to the next step without further purification.

ステップ３：
トルエン（３００ｍＬ）中のステップ２の生成物の溶液に、ヨウ化トリメチルシリル（２１ｍＬ、１５２．４ｍｍｏｌ）をゆっくり加えた。得られた反応混合物を３時間撹拌した。その反応物を次にＭｅＯＨ（１２．４ｍＬ、３０５ｍｍｏｌ）により失活させ、１５％のＮａＨＳＯ_３水溶液（２００ｍｌ）で、続いて飽和ＮａＨＣＯ_３水溶液（２００ｍＬ）により連続して洗浄した。式ＸＩＩＩの遊離塩基のその粗生成物を含有する有機層をさらなる精製はせずに次の段階にそのまま持ち込んだ。

Step 3:
To a solution of the product of Step 2 in toluene (300 mL) was slowly added trimethylsilyl iodide (21 mL, 152.4 mmol). The resulting reaction mixture was stirred for 3 hours. The reaction was then quenched with MeOH (12.4 mL, 305 mmol) and washed sequentially with 15% aqueous NaHSO ₃ (200 ml) followed by saturated aqueous NaHCO ₃ (200 mL). The organic layer containing the crude product of the free base of Formula XIII was taken directly to the next step without further purification.

Step 4:
To the crude product in toluene from step 3 above, maleic acid (18 g, 155 mmol) dissolved in MeOH (50 mL) was added. The resulting mixture was stirred for 1 hour. The amount of the resulting solution was then reduced to 100 mL at 40 ° C. under vacuum distillation. At 40 ° C., n-heptane (100 mL) was added to the resulting solution. Upon cooling to RT, maleate crystallization occurred and additional n-heptane (500 mL) was added. After stirring for 2 hours, the solid was filtered and washed with toluene (400 mL), n-heptane (200 mL) and water (250 mL). The wet cake was dried under vacuum at 45 ° C. for 12 hours to give the compound of formula IVa (61 g, 77% yield according to 6197734-D). Melting point: 135 ° C to 140 ° C.

液体クロマトグラフ質量分析（ＬＣ−ＭＳ）［Ｃ_２０Ｈ_２０Ｆ_６ＮＯ^＋］に対して計算した正確な質量 計算値：４０４．１４４３６、実測値：４０４．１４４５６。

Liquid chromatography mass spectrometry _{(LC-MS) [C 20} H 20 F 6 NO +] Exact mass calcd calculated for: 404.14436, found: 404.14456.

  (Example 2)

［（１Ｓ）−１−（｛（１Ｒ）−１−［３，５−ビス（トリフルオロメチル）フェニル］エトキシ｝メチル）−１−フェニルプロプ−２−エニル］アミン塩酸一水和物。
実施例１からのステップ３の粗生成物（遊離塩基）のトルエンの溶液に、濃ＨＣｌ（１３ｍＬ、１５６ｍｍｏｌ、水中３７％）を加えた。１時間撹拌後、得られた混合物の量を真空蒸留下で、４０℃で２００ｍＬまで減少させ、次に水（６．６ｍＬ、４６５ｍｍｏｌ）を加えた。ＲＴまで冷却した後、ｎ−ヘプタン（７００ｍＬ）をゆっくり加えた。得られたスラリーを、ＲＴで６時間撹拌し、次に０℃に冷却し、さらに６時間撹拌した。その生成物を濾過し、ｎ−ヘプタン（２００ｍＬ）で洗浄し、真空下の室温で１２時間乾燥して白色固体としてのＩＶｂを提供した（５１．８ｇ、ＸＩからの７３モル％の収率）。融点（分解を伴う）３７℃。

[(1S) -1-({(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} methyl) -1-phenylprop-2-enyl] amine hydrochloride monohydrate.
To a solution of the crude product of Step 3 from Example 1 (free base) in toluene was added concentrated HCl (13 mL, 156 mmol, 37% in water). After stirring for 1 hour, the amount of the resulting mixture was reduced to 200 mL at 40 ° C. under vacuum distillation, then water (6.6 mL, 465 mmol) was added. After cooling to RT, n-heptane (700 mL) was added slowly. The resulting slurry was stirred at RT for 6 hours, then cooled to 0 ° C. and stirred for an additional 6 hours. The product was filtered, washed with n-heptane (200 mL) and dried at room temperature under vacuum for 12 hours to provide IVb as a white solid (51.8 g, 73 mol% yield from XI) . Melting point (with decomposition) 37 ° C.

（実施例３）

(Example 3)

ステップ１：
（３Ｒ，６Ｓ）−３−ｔｅｒｔ−ブチルジヒドロ−１Ｈ−ピロロ［１，２−ｃ］［１，３］オキサゾール−１，５（６Ｈ）−ジオンの調製

Step 1:
Preparation of (3R, 6S) -3-tert-butyldihydro-1H-pyrrolo [1,2-c] [1,3] oxazole-1,5 (6H) -dione

方法（ａ）
撹拌器、温度計、ディーンスターク還流冷却器、および窒素導入管を備えた２５０ｍＬの三つ口フラスコに、Ｌ−ピログルタミン酸（２０．０ｇ、１５４．８ｍｍｏｌ）、トルエン（６０ｍＬ）、ジエチレングリコールジメチルエーテル（６０ｍＬ）、トリメチルアセトアルデヒド（４０．０ｇ、４６４．４ｍｍｏｌ）、およびＣＨ_３ＳＯ_３Ｈ（１．５ｇ、１５．６ｍｍｏｌ）を加えた。その反応混合物を、１０２〜１２０℃（還流）で１４．５時間、すなわち、ディーンスターク装置により水を除去して反応が完了するまで、加熱して還流した。その反応混合物を３５℃まで冷却し、真空下で５０ｍＬの最終的な量まで蒸留した。その混合物を１時間かけて２０℃まで冷却し、ｎ−ヘプタン（１４０ｍＬ）を１時間かけて加えた。その反応混合物を１時間かけて−５℃まで冷却し、１時間撹拌した。そのスラリーを濾過し、ヘプタン（６０ｍＬ）および水（６０ｍＬ）により洗浄し、真空下５０℃で乾燥して、オフホワイト結晶固体としてのＸＩＶを提供した（２３．９ｇ、７９％の収率）。融点（分解を伴う）１１６〜１６８℃。

Method (a)
To a 250 mL three-necked flask equipped with a stirrer, thermometer, Dean-Stark reflux condenser, and nitrogen inlet tube was added L-pyroglutamic acid (20.0 g, 154.8 mmol), toluene (60 mL), diethylene glycol dimethyl ether (60 mL). ), Trimethylacetaldehyde (40.0 g, 464.4 mmol), and CH ₃ SO ₃ H (1.5 g, 15.6 mmol) were added. The reaction mixture was heated to reflux at 102-120 [deg.] C. (reflux) for 14.5 hours, i.e. until the reaction was complete by removing water with a Dean-Stark apparatus. The reaction mixture was cooled to 35 ° C. and distilled under vacuum to a final volume of 50 mL. The mixture was cooled to 20 ° C. over 1 hour and n-heptane (140 mL) was added over 1 hour. The reaction mixture was cooled to −5 ° C. over 1 hour and stirred for 1 hour. The slurry was filtered, washed with heptane (60 mL) and water (60 mL) and dried under vacuum at 50 ° C. to provide XIV as an off-white crystalline solid (23.9 g, 79% yield). Melting point (with decomposition) 116-168 ° C.

ＬＣ／ＭＳ Ｃ_１０Ｈ_１６ＮＯ_３（Ｍ＋Ｈ）^＋（ｍ／ｚ）に対する計算値：１９７．２３１、実測値：１９７．２２７。

_{LC / MS C 10 H 16 NO} 3 (M + H) + calcd for (m / z): 197.231, found: 197.227.

Method (b):
In a 250 mL three-necked flask equipped with a stirrer, thermometer, reflux condenser, and nitrogen inlet tube, L-pyroglutamic acid (200 g, 1.6 mol), NMP (400 mL), trimethylacetaldehyde (500 mL, 397 g, 4 .6mol), and _{CH 3 SO 3 H (30mL,} 44.5g, 0.46mol) was added. The reaction mixture was heated to 82.5 ° C. (reflux) for 15 minutes and TFAA (240 mL, 1.11 equiv) was added slowly over 4.5 hours. The temperature was maintained at 82.5 ° C. for an additional 4.5 hours. The flask was cooled to 20 ° C. over 1 hour and the mixture was transferred to a 5 ° C. slurry of NaHCO ₃ (325 g, 3.9 mmol) in water (2 L) over 1 hour. The slurry was filtered and washed with ice cold water (400 mL). The wet cake was then dried under vacuum at 50 ° C. to provide XIV as an off-white crystalline solid (244 g, 72% yield).

  Method (c):

撹拌器、温度計、還流冷却器、および窒素導入管を備えた２５０ｍＬの三つ口フラスコに、Ｌ−ピログルタミン酸（２５０ｇ、１．９４ｍｏｌ）、トルエン（１０００ｍＬ）、および（ＣＨ_３）_３ＳｉＮＨＳｉ（ＣＨ_３）_３（８９０ｍＬ、４．２６ｍｏｌ）を加えた。その混合物を加熱して６時間にわたって還流させ、その間に、還流温度は８０℃から１００℃までゆっくりと上昇した。６時間後、その混合物を８０ｍｍＨｇおよび５０℃で４００ｍＬの量まで蒸留した。追加のトルエン（１０００ｍＬ）を入れ、その混合物を真空中で４００ｍＬの量まで蒸留した。次にトリメチルアセトアルデヒド（５００ｍＬ、３９７ｇ，４．６ｍｏｌ）、およびＣＨ_３ＳＯ_３Ｈ（３０ｍＬ、４４．５ｇ、０．４６ｍｏｌ）を入れ、その反応混合物を９０℃に４時間にわたって加熱した。その反応混合物を３５℃に冷却し、トルエン（１２００ｍＬ）を加え、その混合物を真空下で１０００ｍＬの最終量まで蒸留した。そのフラスコを２０℃まで冷却し、その混合物を、ＮａＨＣＯ_３（６５ｇ）の水（１２５０Ｌ）の中の溶液に−５℃で１時間かけて移した。そのスラリーを濾過し、氷冷水（４００ｍＬ）で、次いで氷冷したイソプロピルアルコール（１００ｍＬ）で洗浄した。そのウェットケーキを次に真空下５０℃で乾燥し、オフホワイト結晶固体としての式ＸＩＶの化合物を提供した（２６７ｇ、６８％の収率）。

To a 250 mL three-necked flask equipped with a stirrer, thermometer, reflux condenser, and nitrogen inlet tube was added L-pyroglutamic acid (250 g, 1.94 mol), toluene (1000 mL), and (CH ₃ ) ₃ SiNHSi ( _{CH 3) 3 (890mL, 4.26mol} ) was added. The mixture was heated to reflux for 6 hours, during which time the reflux temperature rose slowly from 80 ° C to 100 ° C. After 6 hours, the mixture was distilled at 80 mm Hg and 50 ° C. to a volume of 400 mL. Additional toluene (1000 mL) was charged and the mixture was distilled in vacuo to a volume of 400 mL. Then trimethylacetaldehyde (500 mL, 397 g, 4.6 mol) and CH ₃ SO ₃ H (30 mL, 44.5 g, 0.46 mol) were charged and the reaction mixture was heated to 90 ° C. for 4 hours. The reaction mixture was cooled to 35 ° C., toluene (1200 mL) was added and the mixture was distilled under vacuum to a final volume of 1000 mL. The flask was cooled to 20 ° C. and the mixture was transferred to a solution of NaHCO ₃ (65 g) in water (1250 L) at −5 ° C. over 1 hour. The slurry was filtered and washed with ice cold water (400 mL) followed by ice cold isopropyl alcohol (100 mL). The wet cake was then dried under vacuum at 50 ° C. to provide the compound of formula XIV as an off-white crystalline solid (267 g, 68% yield).

  Method (d):

撹拌器、温度計、還流冷却器、および窒素導入管を備えた１Ｌの三つ口フラスコに、Ｌ−ピログルタミン酸（５０ｇ、０．３９ｍｏｌ）、トルエン（４５０ｍＬ）およびＥｔ_３Ｎ（１１３ｍＬ、０．８１ｍｏｌ）を仕込んだ。温度を３０℃より下に保ちながら、（ＣＨ_３）_３ＳｉＣｌ（１０３ｍＬ、０．８１ｍｏｌ）を加えた。その混合物を１１０℃まで加熱し、３時間にわたって撹拌した。その懸濁液を５℃まで冷却し、ヘプタン（１００ｍＬ）で希釈した。トリエチルアンモニウム塩酸塩を濾過によって除去し、トルエン／ヘプタン溶液（２００ｍＬ）により洗浄した。その濾液を１５０ｍＬの最終量まで濃縮し、ＮＭＰ（５０ｍＬ）、トリメチルアセトアルデヒド（１００ｍＬ、０．７８ｍｏｌ）およびＣＨ_３ＳＯ_３Ｈ（２．５ｍＬ、０．０４ｍｏｌ）を加えた。その反応混合物を８０℃に２４時間にわたって加熱し、次いで４０℃まで冷却した。その反応混合物を約１００ｍＬまで濃縮し、アセトン（１００ｍＬ）で希釈した。その反応混合物を、水（２５０ｍＬ）中のＮａＨＣＯ_３（１３ｇ）の２０℃の溶液に移した。その懸濁液を５℃まで冷却し、１時間撹拌した。そのスラリーを濾過し、氷冷水（５０ｍＬ）で、次いで氷冷したイソプロピルアルコール（５０ｍＬ）で洗浄した。その生成物を次に真空下４５℃で乾燥し、オフホワイト結晶固体としてのＸＩＶを提供した（４８．３ｇ、６３％）。

To a 1 L three-necked flask equipped with a stirrer, thermometer, reflux condenser, and nitrogen inlet tube was added L-pyroglutamic acid (50 g, 0.39 mol), toluene (450 mL), and Et ₃ N (113 mL, 0.3 mL). 81 mol) was charged. (CH ₃ ) ₃ SiCl (103 mL, 0.81 mol) was added while keeping the temperature below 30 ° C. The mixture was heated to 110 ° C. and stirred for 3 hours. The suspension was cooled to 5 ° C. and diluted with heptane (100 mL). Triethylammonium hydrochloride was removed by filtration and washed with a toluene / heptane solution (200 mL). The filtrate was concentrated to a final volume of 150 mL and NMP (50 mL), trimethylacetaldehyde (100 mL, 0.78 mol) and CH ₃ SO ₃ H (2.5 mL, 0.04 mol) were added. The reaction mixture was heated to 80 ° C. for 24 hours and then cooled to 40 ° C. The reaction mixture was concentrated to about 100 mL and diluted with acetone (100 mL). The reaction mixture was transferred to a 20 ° C. solution of NaHCO ₃ (13 g) in water (250 mL). The suspension was cooled to 5 ° C. and stirred for 1 hour. The slurry was filtered and washed with ice cold water (50 mL) followed by ice cold isopropyl alcohol (50 mL). The product was then dried under vacuum at 45 ° C. to provide XIV as an off-white crystalline solid (48.3 g, 63%).

  Method (e):

撹拌器、温度計、還流冷却器、および窒素導入管を備えた１Ｌの三つ口フラスコに、Ｌ−ピログルタミン酸（２０ｇ、０．１６ｍｏｌ）、トリメチルアセトアルデヒド（５０ｍＬ、０．３９ｍｏｌ）、メタンスルホン酸（１．４ｍＬ、０．０２ｍｏｌ）、トルエン（１４０ｍＬ）およびＮ−メチルピロリドン（２０ｍＬ）を仕込んだ。その混合物を９０℃まで加熱し、９０℃に維持してその間に無水トリフルオロ酢酸（２７ｍＬ）をゆっくり添加した。その反応物を９０℃で８時間維持して酸の１００％の変換率を達成した。

In a 1 L three-necked flask equipped with a stirrer, thermometer, reflux condenser, and nitrogen inlet tube, L-pyroglutamic acid (20 g, 0.16 mol), trimethylacetaldehyde (50 mL, 0.39 mol), methanesulfonic acid (1.4 mL, 0.02 mol), toluene (140 mL) and N-methylpyrrolidone (20 mL) were charged. The mixture was heated to 90 ° C. and maintained at 90 ° C. during which time trifluoroacetic anhydride (27 mL) was added slowly. The reaction was maintained at 90 ° C. for 8 hours to achieve 100% acid conversion.

  Step 2:

撹拌器、温度計、還流冷却器、および窒素導入管を備えた２Ｌの三つ口フラスコに、ＸＩＶ（１００ｇ、０．５ｍｏｌ）、ＣｕＣｌ（１０ｇ）、ＤＭＩ（１００ｍＬ）、ＴＨＦ（１．２Ｌ）、およびギ酸メチル（１００ｍＬ）を仕込んだ。［−６０］℃より下まで冷却した後、ＬＨＭＤＳ（７００ｍＬ、ＴＨＦ中１．０Ｍ）を、温度が−６０℃を超えない速度で加えた。ＬＨＭＤＳの添加後、ＴＭＳＣＩを、温度が［−６０］℃を超えない速度で加えた。その混合物を０℃と１０℃の間の温度に３０分かけて温め、そのバッチを真空中で２５０ｍＬまで濃縮し、ＥｔＯＡｃ（３００ｍＬ）を加えた。クエン酸（１２０ｇ）、水（１Ｌ）、およびＥｔＯＡｃ（１Ｌ）の５℃の混合物に、次いで、その粗製の反応混合物を、温度を０℃と１５℃の間に維持しながら３０分間かけて移した。その粗混合物を含有するフラスコを、次にＥｔＯＡｃ（２００ｍＬ）ですすいだ。１０分間撹拌した後、層分離し、有機層を、１２．５％クエン酸水（８００ｍＬ）、１０％クエン酸水（７００ｍＬ）および８％クエン酸水溶液（６００ｍＬ）で連続して洗浄した。その有機層と水（３００ｍＬ）の５℃の混合物に、トリフルオロ酢酸（３０ｍＬ）を、温度を５℃と１５℃の間に維持しながら１０分間かけて加えた。その添加が完了した後、その混合物を２５℃に温め、３．５時間撹拌した。ＫＨＣＯ_３（２００ｍＬ、２０％）の水溶液を、温度を２０℃より下に維持しながら３０分間かけて加え、続いて飽和ＮａＣｌ溶液（５００ｍＬ）を加え、層分離して分割した。その水層をＥｔＯＡｃ（２５０ｍＬ）により逆抽出した。そのＥｔＯＡｃ画分を飽和ＮａＣｌ溶液（５００ｍＬ）で洗浄した。その合わせた有機層に水（３５ｍＬ）を加え、その溶液を真空中で１００ｍＬの最終量まで濃縮した。ＭＴＢＥ（４００ｍＬ）を加え、その混合物を真空中で１００ｍＬの最終量まで濃縮した。追加のＭＴＢＥ（４００ｍＬ）を加え、その懸濁液をＲＴで２時間にわたって撹拌した。得られたスラリーを濾過し、ＭＴＢＥ（２００ｍＬ）ですすぎ、真空中４５℃で１２時間乾燥した後、ＸＶを６１％の収率（７０ｇ）で得た。融点１９６℃〜１９８℃。

To a 2 L three-necked flask equipped with a stirrer, thermometer, reflux condenser, and nitrogen inlet tube, XIV (100 g, 0.5 mol), CuCl (10 g), DMI (100 mL), THF (1.2 L) , And methyl formate (100 mL). After cooling below [−60] ° C., LHMDS (700 mL, 1.0 M in THF) was added at a rate such that the temperature did not exceed −60 ° C. Following the addition of LHMDS, TMSCI was added at a rate such that the temperature did not exceed [−60] ° C. The mixture was warmed to a temperature between 0 ° C. and 10 ° C. over 30 minutes, the batch was concentrated in vacuo to 250 mL and EtOAc (300 mL) was added. To a 5 ° C. mixture of citric acid (120 g), water (1 L), and EtOAc (1 L) is then transferred over 30 minutes while maintaining the temperature between 0 ° C. and 15 ° C. did. The flask containing the crude mixture was then rinsed with EtOAc (200 mL). After stirring for 10 minutes, the layers were separated and the organic layer was washed successively with 12.5% aqueous citric acid (800 mL), 10% aqueous citric acid (700 mL), and 8% aqueous citric acid (600 mL). To a 5 ° C. mixture of the organic layer and water (300 mL), trifluoroacetic acid (30 mL) was added over 10 minutes while maintaining the temperature between 5 ° C. and 15 ° C. After the addition was complete, the mixture was warmed to 25 ° C. and stirred for 3.5 hours. An aqueous solution of KHCO ₃ (200 mL, 20%) was added over 30 minutes while maintaining the temperature below 20 ° C., followed by addition of saturated NaCl solution (500 mL), and the layers were separated. The aqueous layer was back extracted with EtOAc (250 mL). The EtOAc fraction was washed with saturated NaCl solution (500 mL). Water (35 mL) was added to the combined organic layers and the solution was concentrated in vacuo to a final volume of 100 mL. MTBE (400 mL) was added and the mixture was concentrated in vacuo to a final volume of 100 mL. Additional MTBE (400 mL) was added and the suspension was stirred at RT for 2 hours. The resulting slurry was filtered, rinsed with MTBE (200 mL), and dried in vacuo at 45 ° C. for 12 hours before obtaining XV in 61% yield (70 g). Melting point: 196 ° C-198 ° C.

ＥＳ−ＭＳ：［Ｍ＋Ｈ^＋］Ｃ_１１Ｈ_１５ＮＯ_４に対する計算値：２２６．１０、実測値：２２６．２７
ステップ３：

ES-MS: Calculated for [M + H ⁺ ] C ₁₁ H ₁₅ NO ₄ : 226.10, found: 226.27
Step 3:

温度計および機械撹拌器を備えた三つ口の１Ｌフラスコに、Ｐｈ_３ＰＣＨ_３Ｂｒ（１２２．９ｇ、３４４．１ｍｍｏｌ）およびトルエン（１００ｍＬ）を仕込んだ。１０℃でＮａＨＭＤＳのトルエン中の溶液（５４０ｍＬ、１３％）をゆっくり加え、温度を１０℃に維持した。このスラリーを１０℃で１時間撹拌し、次に、トルエン（１００ｍＬ）中のＸＶ（５０ｇ、２２２ｍｍｏｌ）の１０℃のスラリーに蠕動ポンプにより２〜４時間をかけてゆっくり加えた。さらに１時間撹拌した後、そのバッチを、ＮａＣｌ（１０％水溶液）、ＡｃＯＨ（３８．５ｍＬ、６６６ｍｍｏｌ）、およびトルエン（５０ｍＬ）の溶液中に２５℃で３０分かけて入れて失活させた。得られた混合物を３０分間撹拌し、層を安定させ、分割して下の水層を除去した。有機層を、次に、ＭｇＣｌ_２粉末（７０ｇ、７７６ｍｍｏｌ）によりＲＴで２時間処理した。その固体を次に濾別し、固体のＭｇＣｌ_２−トリフェニルホスフィンオキシド錯体を、ＭＴＢＥ（１００ｍＬ）で洗浄した。その有機濾液を合わせ、ＮａＣｌ水（１００ｍＬ、１０％）で洗浄し、真空中で１００ｍＬまで濃縮した。得られたスラリーにヘプタン（４００ｍＬ）を加え、その容量を真空中で１００ｍＬまで減少させた。追加のヘプタン（４００ｍＬ）を加え、その容量を真空中で２５０ｍＬまで減少させた。ヘプタンの第３の分（４００ｍＬ）を加え、そのバッチを次に０℃まで２時間かけて冷却し、この温度でさらに２時間撹拌した。その固体を次に濾過によって除去し、氷冷Ｎ−ヘプタン（２００ｍＬ）で洗浄した。そのウェットケーキを真空下３０℃で１８時間乾燥して、オフホワイト固体としての６２ｇのＸＶＩ（６３％の収率）を生成した。融点８５℃〜８７℃。

A three-neck 1 L flask equipped with a thermometer and a mechanical stirrer was charged with Ph ₃ PCH ₃ Br (122.9 g, 344.1 mmol) and toluene (100 mL). A solution of NaHMDS in toluene (540 mL, 13%) was slowly added at 10 ° C. to maintain the temperature at 10 ° C. This slurry was stirred at 10 ° C. for 1 hour and then slowly added to a 10 ° C. slurry of XV (50 g, 222 mmol) in toluene (100 mL) via a peristaltic pump over 2-4 hours. After stirring for an additional hour, the batch was quenched by placing in a solution of NaCl (10% aqueous solution), AcOH (38.5 mL, 666 mmol), and toluene (50 mL) at 25 ° C. over 30 minutes. The resulting mixture was stirred for 30 minutes to stabilize the layer and split to remove the lower aqueous layer. The organic layer was then treated with MgCl ₂ powder (70 g, 776 mmol) at RT for 2 hours. The solid was then filtered off and the solid MgCl ₂ -triphenylphosphine oxide complex was washed with MTBE (100 mL). The organic filtrates were combined, washed with aqueous NaCl (100 mL, 10%) and concentrated in vacuo to 100 mL. To the resulting slurry was added heptane (400 mL) and the volume was reduced to 100 mL in vacuo. Additional heptane (400 mL) was added and the volume was reduced to 250 mL in vacuo. A third portion of heptane (400 mL) was added and the batch was then cooled to 0 ° C. over 2 hours and stirred at this temperature for an additional 2 hours. The solid was then removed by filtration and washed with ice cold N-heptane (200 mL). The wet cake was dried under vacuum at 30 ° C. for 18 hours to produce 62 g of XVI (63% yield) as an off-white solid. Melting point 85 ° C. to 87 ° C.

ＥＳ−ＭＳ：［Ｍ＋Ｈ^＋］Ｃ_１２Ｈ_１８ＮＯ_３に対する計算値：２２４．１２、実測値：２２４．３８。

_{^{ES-MS: [M + H}} +] calcd for _{C 12 H 18 NO 3: 224.12} , Found: 224.38.

Step 4:
To a 500 mL three-necked flask (1) equipped with a stirrer, thermometer, and nitrogen inlet tube, XIV (30.0 g, 132 mmol) and THF (300 mL) were added. After the mixture was cooled to −20 ° C., lithium tri (t-butoxy) aluminum hydride (1M THF, 162 mL) was added over 2 hours while maintaining the temperature around −20 ° C. The temperature was then raised to 0 ° C. over 12 hours. The reaction was quenched by adding EtOAc (12.0 mL) over 30 minutes, followed by stirring at 0 ° C. for 30 minutes, and then slowly adding ice AcOH (12.0 mL) over 30 minutes. In a separate 1 L three-necked flask (2) equipped with a stirrer, thermometer and nitrogen inlet tube, finely ground sodium sulfate decahydrate (30 g, 93 mol) and THF (150 mL) at 0 ° C. added. The reaction mixture in flask (1) was slowly transferred to flask (2) containing sodium sulfate decahydrate while maintaining the temperature at 0 ° C. The temperature of the flask (2) was raised over 1 hour and stirred at 20 ° C. for 1 hour. The contents of flask (2) were filtered, the wet cake was washed three times with THF (180 mL, 120 mL, and then 120 mL), and the filtrates were combined and concentrated in vacuo to 60 mL. Water (300 mL) was added to a 1000 mL three-necked flask (3) equipped with a stirrer, thermometer, and nitrogen inlet tube. The mixture from flask (2) was cooled to 5 ° C. and then added to the water with vigorous stirring over 2 hours, so that the product precipitated. The slurry was concentrated in vacuo to 450 mL and the solid was isolated by filtration. The wet cake was dried at 50 ° C. for 12 hours to provide 25.1 g of the compound of Formula II as a white / off-white solid in 83% yield. Melting point 88 ° C.

ＬＣ／ＭＳ Ｃ_１２Ｈ_２０ＮＯ_３［Ｍ＋Ｈ］^＋（ｍ／ｚ）に対する質量計算値：２２６．１４３７７、実測値：２２６．１４３９８。

_{LC / MS C 12 H 20 NO} 3 [M + H] + mass calcd for (m / z): 226.14377, found: 226.14398.

  (Example 4)

５（Ｒ）−［［［ｌ（Ｓ）−［［ｌ（Ｒ）−［３，５−ビス（トリフルオロメチル）フェニル］エトキシ］メチル］−ｌ−フェニル−２−プロペニル］アミノ］メチル］−５−エテニル−２−ピロリジノン４−メチルベンゼンスルホネート水和物

5 (R)-[[[l (S)-[[l (R)-[3,5-bis (trifluoromethyl) phenyl] ethoxy] methyl] -l-phenyl-2-propenyl] amino] methyl] -5-ethenyl-2-pyrrolidinone 4-methylbenzenesulfonate hydrate

ａ）ＥｔＯＨ（５０ｍＬ）中のＩＩ（４９．６ｇ、０．２２ｍｏｌ）およびＥｔ_３Ｎ（５０ｍＬ）の混合物に、水（５０ｍＬ）をＲＴで加えた。得られた混合物を２５℃で撹拌した。４時間後、さらなるＥｔＯＨ（３５０ｍＬ）を加え、その混合物を真空中で１８０ｍＬまで濃縮した。
ｂ）トルエン（４４０ｍＬ）中のＩＶａ（１００ｇ、０．１９３ｍｏｌ）の混合物に、ＲＴでＮａＯＨ水溶液（４４０ｍＬ、１Ｎ）を加えた。その反応混合物をＲＴで３０分間撹拌した。その水層を分離し、その有機層を１０％のＮａＣｌ水溶液（４４０ｍＬ）で２回洗浄した。その粗生成物ＩＶ遊離塩基をさらなる精製はしないで使用した。

a) To a mixture of II (49.6 g, 0.22 mol) and Et ₃ N (50 mL) in EtOH (50 mL), water (50 mL) was added at RT. The resulting mixture was stirred at 25 ° C. After 4 hours, additional EtOH (350 mL) was added and the mixture was concentrated in vacuo to 180 mL.
b) To a mixture of IVa (100 g, 0.193 mol) in toluene (440 mL) was added aqueous NaOH (440 mL, 1N) at RT. The reaction mixture was stirred at RT for 30 minutes. The aqueous layer was separated and the organic layer was washed twice with 10% aqueous NaCl (440 mL). The crude product IV free base was used without further purification.

The crude solution of III in EtOH was then added to the above solution of IV free base in toluene and the resulting mixture was heated to reflux. Water was removed from the reaction by azeotropic distillation and additional toluene / EtOH (3/2 v / v) was added if needed based on conversion. After the reaction was complete, EtOH was removed by solvent exchange with toluene and a crude solution of V in toluene (530 mL) was added NaBH (OAc) ₃ (57.3 g, 0.27 mol) and AcOH in toluene (270 mL). To the mixture (15.5 mL, 0.27 mol) was added slowly at RT. The reaction mixture was stirred at RT for about 6 hours, then water (440 mL) was added slowly and the resulting mixture was stirred at RT for 1 hour. The aqueous layer was separated and the organic layer was washed once with 5% aqueous NaHCO ₃ (440 mL) and twice with 10% aqueous NaCl (440 mL) to give a solution of VI. The solvent was exchanged for isopropanol by vacuum distillation.
c) To the crude free base solution of VI in the isopropanol (200 mL) was added a solution of p-toluenesulfonic acid (40.4 g, 0.212 mol) in isopropanol (270 mL) at RT followed by water (440 mL). ) Was added. About 0.5 g of crystalline VIa was added to the mixture as a seed crystal, stirred for 1 hour at RT, and then water (880 mL) was further added. After stirring for 8 hours at RT, the crystals were collected by filtration, washed with isopropanol / water, water and heptane and dried to give VIa as a white crystalline powder (122 g, 88% yield based on V). ). Melting point: 80.2-93.4 ° C.

（実施例５）

(Example 5)

（５Ｒ，８Ｓ）−８−［１−（Ｒ）−（３，５−ビス−トリフルオロメチル−フェニル）−エトキシメチル］−８−フェニル−１，７−ジアザ−スピロ［４．５］デカ−９−エン−２−オン塩酸塩
１３０．０ｇ（１８１．４ｍｍｏｌ）のＶＩａ（ＶＩｐ−トルエンスルホン酸（ＴｓＯＨ）一水和物）および５１．７ｇ（２７２．１ｍｍｏｌ）のトルエンスルホン酸のトルエン（３．２５Ｌ）中の溶液を、減圧下（６０〜８０ｍｍＨｇ）５０℃で、１．９５Ｌの最終量まで蒸留した。蒸留が完了した時点で、ＶＩａおよびトルエンエンスルホン酸を含有するトルエン溶液を約８０ｍｍＨｇまで排気し、次いで液面下に沈めた針によりＮ_２でパージした。このスパージング作業を２回繰り返した。第２の反応器中で、構造

(5R, 8S) -8- [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -ethoxymethyl] -8-phenyl-1,7-diaza-spiro [4.5] deca -9-en-2-one hydrochloride 130.0 g (181.4 mmol) of VIa (VIp-toluenesulfonic acid (TsOH) monohydrate) and 51.7 g (272.1 mmol) of toluenesulfonic acid in toluene ( The solution in 3.25 L) was distilled under reduced pressure (60-80 mm Hg) at 50 ° C. to a final volume of 1.95 L. When the distillation was complete, the toluene solution containing VIa and tolueneene sulfonic acid was evacuated to about 80 mm Hg and then purged with N ₂ with a needle submerged below the surface. This sparging operation was repeated twice. In the second reactor, the structure

を有する１．１４ｇ（１．８ｍｍｏｌ）のＨｏｖｅｙｄａ−Ｇｒｕｂｂｓの第二世代の触媒（ＨＧ−ＩＩ）を無水の脱気したトルエン（６５０ｍＬ、上記のトルエン溶液と全く同様のやり方で調製した）に溶解した。この触媒溶液を、６０℃と８０℃の間の温度で第１の反応器に３０分間かけてゆっくり加えた。その反応混合物を同じ温度範囲で４時間撹拌し、変換率をＨＰＬＣにより測定した。その反応が完了した時点で、１６％のＮａ_２Ｓ_２Ｏ_５水溶液（６５０ｍＬ）をその反応器に３０分間かけて加え、６０〜８０℃で３時間撹拌し、その後その混合物を２５℃まで冷却し、０．５ＮのＮａＨＣＯ_３水溶液（６５０ｍＬ）を加えた。その２相の混合物を次に２５℃で１時間撹拌し、そのまま安定させ、下の水層および界面を除去した。その有機相を０．５ＮのＮａＨＣＯ_３水（１．３Ｌ）により、次に１０％のＮａＣｌ水（１．３Ｌ）により、最後に水（１．３Ｌ）により洗浄した。その有機相をセライトのパッドにより濾過し、その濾液に１２ＮのＨＣｌ水（１４．４ｍＬ）を加えた。そのトルエン／Ｈ_２Ｏを５０℃より上の温度の真空下（５０〜６０ｍｍＨｇ）で３９０ｍＬより少なくなるまで濃縮した。その得られた溶液を４５℃まで冷却し、ヘプタン（６５ｍＬ）中のＶＩＩａを種晶として添加した。４５℃で３０分間撹拌した後、その反応混合物を４５℃から２０℃に６時間かけて冷却した。次いで、ヘプタン（１．８２Ｌ）を２０℃のその反応混合物に３時間かけて加えた。その固体の沈殿を、濾過し、ヘプタン（５２０ｍＬ）により洗浄した。そのウェットケーキを２５℃で４時間、次いで、真空オーブン中６５℃で一晩乾燥して、灰色〜白色固体としての８３ｇのＶＩＩａ（８５％の収率）を提供した。さらに、その水層を、合わせて濾過し、Ｒｕ塩を回収することができる。融点１９０〜１９５℃。

1.14 g (1.8 mmol) of Hoveyda-Grubbs second generation catalyst (HG-II) having a water content in anhydrous degassed toluene (650 mL, prepared in exactly the same manner as the toluene solution above) did. This catalyst solution was slowly added to the first reactor over 30 minutes at a temperature between 60 ° C and 80 ° C. The reaction mixture was stirred at the same temperature range for 4 hours and the conversion was measured by HPLC. When the reaction was complete, 16% Na ₂ S ₂ O ₅ aqueous solution (650 mL) was added to the reactor over 30 minutes and stirred at 60-80 ° C. for 3 hours, after which the mixture was cooled to 25 ° C. And 0.5N aqueous NaHCO ₃ (650 mL) was added. The biphasic mixture was then stirred at 25 ° C. for 1 hour, allowed to settle, and the lower aqueous layer and interface removed. The organic phase was washed with 0.5N aqueous NaHCO ₃ (1.3 L), then with 10% aqueous NaCl (1.3 L) and finally with water (1.3 L). The organic phase was filtered through a pad of celite and 12N aqueous HCl (14.4 mL) was added to the filtrate. The toluene / H ₂ O was concentrated under vacuum (50-60 mm Hg) at a temperature above 50 ° C. to less than 390 mL. The resulting solution was cooled to 45 ° C. and VIIa in heptane (65 mL) was added as seed crystals. After stirring at 45 ° C. for 30 minutes, the reaction mixture was cooled from 45 ° C. to 20 ° C. over 6 hours. Heptane (1.82 L) was then added to the reaction mixture at 20 ° C. over 3 hours. The solid precipitate was filtered and washed with heptane (520 mL). The wet cake was dried at 25 ° C. for 4 hours and then in a vacuum oven at 65 ° C. overnight to provide 83 g of VIIa (85% yield) as a gray to white solid. In addition, the aqueous layers can be combined and filtered to recover the Ru salt. Melting point 190-195 ° C.

ＥＳ−ＭＳ：Ｃ_２５Ｈ_２５Ｆ_６Ｎ_２Ｏ_２に対して計算した［Ｍ＋Ｈ^＋］：４９９．１８；実測値：４９９．０５。

_ES-MS: calculated for _{C 25 H 25 F 6 N 2} O 2 [M + H +]: 499.18; Found: 499.05.

(Example 5a)
Reduction of metathesis catalyst in the presence of PTC Example 5 was repeated as described above until HPLC showed complete conversion of the compound of formula VIa to the compound of formula VIIa. When the reaction was complete, was added along with chloride tetra -n- butylammonium 2.5 g 16% of _Na 2 _S 2 _{O 5} solution of (650 mL) over a period of 30 minutes to the reactor. The temperature of the reaction mixture was maintained between 60 ° C. and 80 ° C. and the mixture was stirred for 0.7 hours, after which the mixture was cooled to 25 ° C. and 0.5N aqueous NaHCO ₃ solution (650 mL) was added. added. The biphasic mixture was then stirred at 25 ° C. for 1 hour, allowed to settle, the underlying aqueous layer and interface were removed, and the reaction mixture was worked up as described in Example 5. The results were similar and demonstrated the advantages provided by the use of PTC in the reduction of the metathesis catalyst by the process of Scheme 4 described hereinabove.

  (Example 6)

（５Ｓ，８Ｓ）−８−［１−（Ｒ）−（３，５−ビス−トリフルオロメチル−フェニル）−エトキシメチル］−８−フェニル−１，７−ジアザ−スピロ［４．５］デカン−２−オン塩酸水和物
トルエン（６００ｍＬ）中のＶＩＩａ（１００ｇ、０．１８７ｍｏｌ）の混合物に、ＮａＯＨ水（５％、３００ｍＬ）を加えた。その混合物を１５分間撹拌した後、有機層を分離し、ブライン（１０％、２×５００ｍＬ）で洗浄した。その有機層を次にＰｄ／Ｃ（１０ｇ、５０％ウェットのカーボン中１０％）およびＮｕｃｈａｒ−Ａｑｕａｑｕａｒｄ（５０ｇ）により６０〜８０ｐｓｉで４〜８時間または反応が完了するまで水素化にかけた。その反応物をセライトのパッドにより濾過した。そのセライトをトルエン（１００ｍＬ）で洗浄した。その合わせたトルエン溶液を５００ｍＬまで濃縮した。ＨＣｌ水溶液（約３５％、２０ｍｌ、約１．３当量）をその反応溶液中にゆっくり加え、その混合物を０℃までゆっくり冷却した。その生成物を濾過によって集め、トルエンおよびＭＴＢＥの溶液（１：１）により洗浄した。そのウェットケーキを４０〜４５℃で乾燥して９５ｇの白色〜オフホワイトの固体としてのＶＩＩＩを生じさせた（９５％の収率）。融点１５２〜１５４℃。

(5S, 8S) -8- [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -ethoxymethyl] -8-phenyl-1,7-diaza-spiro [4.5] decane 2-one hydrochloric acid hydrate To a mixture of VIIa (100 g, 0.187 mol) in toluene (600 mL) was added aqueous NaOH (5%, 300 mL). After the mixture was stirred for 15 minutes, the organic layer was separated and washed with brine (10%, 2 × 500 mL). The organic layer was then hydrogenated with Pd / C (10 g, 10% in 50% wet carbon) and Nuchar-Aquaquard (50 g) at 60-80 psi for 4-8 hours or until the reaction was complete. The reaction was filtered through a pad of celite. The celite was washed with toluene (100 mL). The combined toluene solution was concentrated to 500 mL. Aqueous HCl (about 35%, 20 ml, about 1.3 eq) was slowly added into the reaction solution and the mixture was slowly cooled to 0 ° C. The product was collected by filtration and washed with a solution of toluene and MTBE (1: 1). The wet cake was dried at 40-45 ° C. to yield VIII as a white to off-white solid (95% yield). Mp 152-154 ° C.

（実施例７）

(Example 7)

（５Ｓ，８Ｓ）−８−（１−（Ｒ）−［３，５−ビス（トリフルオロメチル）フェニル］エトキシ）メチル）−８−フェニル−１，７−ジアザスピロ［４．５］デカン−２−オン塩酸一水和物
方法１：ＶＩＩＩ（２０ｇ）を、１５５．０ｇのＥｔＯＨ−イソプロパノール−水−ＨＣｌ原液（原液作製：１６８．６ｇの無水ＥｔＯＨ、３６８．７ｇの水、１１．６ｇのイソプロパノール、１．６ｇの３７％ＨＣｌ）中に懸濁させ、透明な溶液が得られるまで加熱して還流（７８〜７９℃）させた。その混合物を次に７２℃と７３℃の間の温度にゆっくり冷却し、場合によって、２０ｍｌの原液中に懸濁させた０．４ｇの微粉化したＩａを種晶として添加した。使用するその種晶の量は、生成物の粒径分布（ＰＳＤ）に変化を生じさせるために０．０と２．０ｇの間で変えることができる。そのバッチはさらに０．５℃／分の速さで０℃まで冷却し、真空下で濾過し、４０ｍＬの原液により洗浄した。最後にそのバッチは、真空下４０℃の温度で少なくとも１８時間乾燥し、１８．７ｇの白色固体としてのＩａを生じさせた（９１．２％）。

(5S, 8S) -8- (1- (R)-[3,5-bis (trifluoromethyl) phenyl] ethoxy) methyl) -8-phenyl-1,7-diazaspiro [4.5] decane-2 ON Hydrochloric Acid Monohydrate Method 1: VIII (20 g) was added to 155.0 g EtOH-isopropanol-water-HCl stock solution (stock preparation: 168.6 g anhydrous EtOH, 368.7 g water, 11.6 g isopropanol , 1.6 g of 37% HCl) and heated to reflux (78-79 ° C.) until a clear solution was obtained. The mixture was then slowly cooled to a temperature between 72 ° C. and 73 ° C. and optionally 0.4 g of finely divided Ia suspended in 20 ml of the stock solution was added as seed crystals. The amount of seed crystals used can vary between 0.0 and 2.0 g to produce a change in the particle size distribution (PSD) of the product. The batch was further cooled to 0 ° C. at a rate of 0.5 ° C./min, filtered under vacuum and washed with 40 mL stock solution. Finally, the batch was dried under vacuum at a temperature of 40 ° C. for at least 18 hours, yielding 18.7 g of Ia as a white solid (91.2%).

  Method 2: Suspend 30 grams of VIII in 231 to 232 g of 40:60 volume% EtOH-water stock solution (stock preparation: 400 mL EtOH (95% EtOH, 5% MeOH), 600 mL water). Heated to reflux (78-79 ° C.) until a clear solution was obtained. The mixture was then slowly cooled to a temperature between 67.5 ° C. and 68.5 ° C. and 1.5 g of finely divided Ia suspended in 30 mL of the stock solution was added as seed crystals. The amount of seed crystals used can vary between 0.0 and 3.0 g to produce a change in the product PSD. The batch was further cooled to 0 ° C. at a rate of 0.5 ° C./min and 35 g additional water was added to improve the yield. The batch was filtered under vacuum and washed with 60 mL of a 35:65 volume ratio EtOH: water solution. Finally, the batch was dried under vacuum at a temperature of 40 ° C. for at least 18 hours to produce 28.2-28.9 g of Ia (89.6-91.8%).

  Method 3: VIII (11.6 g) was dissolved in EtOH (47 mL) at RT. Water (186 mL) was added to the solution over about 35 minutes and the temperature of the suspension was maintained at 25 ° C. The resulting suspension was cooled to 0 ° C. and stirred for 30 minutes to improve the yield. The batch was then filtered under vacuum and washed with 25 mL of 20:80 volume ratio EtOH: water solution. Finally, the batch was dried under vacuum at a temperature of 40 ° C. for at least 18 hours. Yield: 9.7 g (83.6%).

  Method 4: VIII (22.9 g) was dissolved in EtOH (76 mL) at RT. The solution was then filtered and water (366.8 g) was added over about 25 minutes. The resulting suspension was cooled to 0 ° C. and stirred for 30 minutes to improve the yield. The batch was then filtered under vacuum and washed with 70 mL of a 20:80 volume ratio EtOH: water solution. Finally, the batch was dried under vacuum at a temperature of 40 ° C. for at least 18 hours. Yield: 20.4 g (89.1%).

  Method 5: VIII (16.4 g) was suspended in toluene (115 mL) at 25 ° C. 50 mL of 1N NaOH solution was added to the suspension and the batch was stirred for 30-60 minutes. The batch was then allowed to separate for about 30 minutes to remove the bottom water layer. 2.82 g of 37% HCl was added to the organic layer to form Ia hydrochloride monohydrate and precipitate. The batch was stirred for 30 minutes, then filtered under vacuum and washed with toluene (32 mL). Finally, the batch was dried under vacuum at a temperature of 40 ° C. for at least 18 hours to provide 12.4 g of Ia (75.6%).

  Using similar procedures, isomers Ib-Ih were prepared. The physical data for these compounds is as follows.

Formula Ib (S, R, R):
Isolated as a light brown oil after column chromatography.

ＭＳ．Ｃ_２５Ｈ_２６Ｆ_６Ｎ_２Ｏ_２−ＨＣｌ．Ｈ_２Ｏに対して計算、（Ｍ＋Ｈ）^＋５００．４７（ｍ／ｚ）：５００．１９。

MS. _{C 25 H 26 F 6 N 2} O 2 -HCl. Calculated for H ₂ O, (M + H) ⁺ 500.47 (m / z): 500.19.

Formula Ic (R, S, R):
Isolated as an off-white solid from diethyl ether.

ＭＳ．Ｃ_２５Ｈ_２６Ｆ_６Ｎ_２Ｏ_２−ＨＣｌ．Ｈ_２Ｏに対して計算、（Ｍ＋Ｈ）^＋５００．４７（ｍ／ｚ）：５００．１８。

MS. _{C 25 H 26 F 6 N 2} O 2 -HCl. Calculated for H ₂ O, (M + H) ⁺ 500.47 (m / z): 500.18.

Formula Id (R, R, R):
Isolated as a off-white solid after purification by column chromatography after trituration in 1: 2 diethyl ether / heptane.

ＭＳ．Ｃ_２５Ｈ_２６Ｆ_６Ｎ_２Ｏ_２−ＨＣｌ．Ｈ_２Ｏに対して計算、（Ｍ＋Ｈ）^＋５００．４７（ｍ／ｚ）：５００．３４。

MS. _{C 25 H 26 F 6 N 2} O 2 -HCl. Calculated for H ₂ O, (M + H) ⁺ 500.47 (m / z): 500.34.

Formula Ie (S, S, S):
Isolated as a fine white HCl salt by column chromatography followed by trituration in diethyl ether at 10 ° C. for 3 hours.

ＭＳ．Ｃ_２５Ｈ_２６Ｆ_６Ｎ_２Ｏ_２−ＨＣｌ．Ｈ_２Ｏに対して計算、（Ｍ＋Ｈ）^＋５００．４７（ｍ／ｚ）：５００．４。

MS. _{C 25 H 26 F 6 N 2} O 2 -HCl. Calculated for H ₂ O, (M + H) ⁺ 500.47 (m / z): 500.4.

Formula If (S, R, S):
After purification by column chromatography, isolated as an off-white HCl salt from diethyl ether.

ＭＳ．Ｃ_２５Ｈ_２６Ｆ_６Ｎ_２Ｏ_２−ＨＣｌ．Ｈ_２Ｏに対して計算、（Ｍ＋Ｈ）^＋５００．４７（ｍ／ｚ）：５００．３。

MS. _{C 25 H 26 F 6 N 2} O 2 -HCl. Calculated for H ₂ O, (M + H) ⁺ 500.47 (m / z): 500.3.

Formula Ig (R, S, S):
Isolated as an off-white HCl salt, purified by column chromatography and then triturated in diethyl ether at 5 ° C. for 12 hours.

ＭＳ．Ｃ_２５Ｈ_２６Ｆ_６Ｎ_２Ｏ_２−ＨＣｌ．Ｈ_２Ｏに対して計算、（Ｍ＋Ｈ）^＋５００．４７（ｍ／ｚ）：５００．３３。

MS. _{C 25 H 26 F 6 N 2} O 2 -HCl. Calculated for H ₂ O, (M + H) ⁺ 500.47 (m / z): 500.33.

Formula Ih (R, R, S):
After purification by column chromatography, it was isolated as the HCl salt by trituration in diethyl ether at 5 ° C. for 3 hours.

ＭＳ．Ｃ_２５Ｈ_２６Ｆ_６Ｎ_２Ｏ_２−ＨＣｌ．Ｈ_２Ｏに対して計算、（Ｍ＋Ｈ）^＋５００．４７（ｍ／ｚ）：５００．３。

MS. _{C 25 H 26 F 6 N 2} O 2 -HCl. Calculated for H ₂ O, (M + H) ⁺ 500.47 (m / z): 500.3.

  The above description of the present invention is intended to be illustrative and not limiting. Various changes or modifications in the embodiments described herein may occur to those skilled in the art. These changes can be made without departing from the scope or spirit of the invention.

Claims (1)

Invention described in the specification.